Pbl Exam 4 Case 4

Front 1

1. Sleep vs. coma

Back 1

Sleep is defined as unconsciousness from which the person can be aroused by sensory or other stimuli.

It is to be distinguished from coma, which is unconsciousness from which the person cannot be aroused.

Front 2

2. What are the two types of sleep?

Back 2

1. Slow wave sleep
2. Rapid eye movement sleep (REM)

Front 3

3. Sleep patterns and types of sleep

Back 3

More sleep during each night is of the slow-wave variety; this is the deep, restful sleep that the person experiences during the first hour of sleep after having been awake for many hours.

REM sleep, on the other hand, occurs in episodes that occupy about 25% of the sleep time in young adults; each episode normally recurs about every 90 minutes. This type of sleep is not so restful, and it is usually associated with vivid dreaming

Front 4

4. Slow wave sleep

Back 4

This sleep is exceedingly restful and is associated with decrease in both peripheral vascular tone and many other vegetative functions of the body.

For instance, there are 10-30% decreased in blood pressure, respiratory rate, and basal metabolic rate.

Front 5

5. Do dreams occur during slow wave sleep?

Back 5

Yes, although SWS is frequently called "dreamless sleep," dreams and sometimes even nightmares do occur during SWS.

The difference between the dreams that occur in SWS and those that occur in REM sleep is that those of REM sleep are associated with more bodily muscle activity, and thus dreams of SWS usually are not remembered.

Also, during SWS, consolidation of the dreams in memory does not occur.

Front 6

6. REM sleep (Paradoxical sleep, desynchronized sleep)

Back 6

REM sleep is a type of sleep in which the brain is quite active. However, the brain activity is not channeled in the proper direction for the person to be fully aware of his or her surroundings, and therefore the person is truly asleep.

Front 7

7. Six characteristics of REM sleep

Back 7

1. It is usually associated with active dreaming and active bodily muscle movements.
2. The person is even more difficult to arouse by sensory stimuli than during deep SWS, and yet people usually awaken spontaneously in the morning during an episode of REM sleep.
3. Muscle tone throughout the body is exceedingly depressed, indicating strong inhibition of the spinal muscle control areas.
4. Heart rate and respiratory rate usually become irregular, which is characteristic of the dream state.
5. Despite the extreme inhibition of the peripheral muscles, irregular muscle movements do occur. These are in addition to the rapid eye movements of the eyes.
6. The brain is highly active in REM sleep, and overall brain metabolism may be increased as much as 20%. The EEG shows a pattern of brain waves similar to those that occur during wakefulness.

Front 8

8. Why is REM sleep called paradoxical sleep?

Back 8

This type of sleep is also called paradoxical sleep b/c it is a paradox that a person can still be asleep despite marked activity in the brain.

Front 9

9. Two theories of sleep

Back 9

1. Passive theory
-The excitatory areas of the upper brain stem, the reticular activating system, simply fatigued during the waking day and became inactive as a result.

2. Sleep is caused by an active inhibitory process
-It was discovered that transecting the brain stem at the level of the midpons creates a brain whose cortex never goes to sleep. In other words, there seems to be some center located below the midpontile level of the brain stem that is required to cause sleep by inhibiting other parts of the brain.

Front 10

10. What are some areas that cause cause sleep in the brain?

Back 10

1. Raphe nuclei in the lower half of the pons and in the medulla. Many nerve endings of fibers from these raphe neurons secrete serotonin

2. Stimulation of some areas in the tractus solitarius can also cause sleep. This nucleus is the termination in the medulla and pons for visceral sensory signals entering by way of the vagus and glossopharyngeal nerves.

3. Stimulation of several regions in the diencephalon can also promote sleep, including the rostral part of the hypothalamus, mainly in the suprachiasmal area, and an occasional area in the diffuse nuclei of the thalamus.

Front 11

11. Discrete lesions in the raphe nuclei

Where can other lesions can produce the same effect?

Back 11

Discrete lesions in the raphe nuclei lead to a high state of wakefulness.

*This is also true of bilateral lesions in the medial rostral suprachiasmal area in the anterior hypothalamus.

Front 12

12. Other possible transmitter substances related to sleep

Back 12

1. Muramyl peptide
-a low molecular weight substance that accumulates in the CSF and urine in animals kept awake for several days.
2. Nonapetide isolated from the blood of sleeping animals
3. Unidentified molecule that has been isolated from the neuronal tissues of the brain stem of animals kept awake for days.

It is possible that prolonged wakefulness causes progressive accumulation of a sleep factor or factors in the brain stem or in the CSF that lead to sleep.

Front 13

13. Possible cause of REM sleep

Back 13

It has been postulated that the large ACh secreting neurons in the upper brain stem reticular formation might, through their extensive efferent fibers, activate many portions of the brain.

This theoretically could cause the excess activity that occurs in certain brain regions in REM sleep, even though the signals are not channeled appropriately int he brain to cause normal conscious awareness that is characteristic of wakefulness.

Front 14

14. Possible mechanism for causing the sleep-wakefulness cycle

Back 14

When the sleep centers are not activated, the mesencephalic and upper pontile reticular activating system are released from inhibition, which allows the reticular activating nuclei to become spontaneously active.

This in turn excites both the cerebral cortex and the peripheral nervous system, both of which send numerous positive feedback signals back to the same reticular activating nuclei to activate them still further.

Then, after the brain remains activated for many hours, even the neurons themselves in the activating system presumably become fatigued.

Consequently, the positive feedback cycle between the mesencephalic reticular nuclei and the cerebral cortex fades, and the seep promoting effects of the sleep centers take over.

Front 15

15. Two major physiologic effects of sleep

Back 15

1. Effects on the nervous system
2. Effects on other functional systems in the body

The principal value of sleep is to restore natural balances among the neuronal centers.

Front 16

16. Brain waves

Back 16

Electrical recordings from the brain; dependent on the activity in respective parts of the cortex.

Much of the time, the brain waves are irregular, and no specific pattern can be discerned in the EEG.

At other times, distinct patterns do appear, some of which are characteristic of specific abnormalities of the brain such as epilepsy.

Front 17

17. Alpha waves

Back 17

Alpha waves are rhythymical waves that occur at frequencies between 8 and 13 Hz and are found in the EEGs of almost all normal adult people when they are awake and in a quiet resting state.

Voltage usually about 50 microvolts. During deep sleep, alpha waves disappear.

Front 18

18. Beta waves

Back 18

The alpha waves are replaced by asynchronous, higher frequency but lower voltage beta waves that occur when the awake person's attention is directed towards some specific type of mental activity.

Beta waves occur at frequencies greater than 14 Hz and as high as 80 Hz.

Front 19

19. Theta waves

Back 19

Theta waves have frequencies between 4 and 7 Hz. They occur normally in the parietal and temporal regiosn in chidlren, but they also occur during emotional stress in some adults, particularly during disappointment and frustration.

Theta waves also occur in many brain disorders, often in degenerative brain states.

Front 20

20. Delta waves

Back 20

Delta waves include all the waves of the EEG with frequencies less than 3.5 Hz, and they often have voltages 2-4x greater than most other types of brain waves.

They occur in very deep sleep, in infancy and in serious organic brain disease. They occur most often in the lower brain.

Front 21

21. How does one determine the intensity of brain waves?

Back 21

The intensity of the brain waves from the scalp is determined mainly by the numbers of neurons and fibers that fire in synchrony with one another, not by the total level of electrical activity in the brain.

In fact, strong nonsynchronous nerve signals often nullify one another.

Front 22

22. Origin of alpha waves

Back 22

Alpha waves will not occur in the cerebral cortex without cortical connections with the thalamus.

It is believed that the alpha waves result from spontaneous feedback oscillation in the diffuse thalamocortical system, possibly including the reticular activating system in the brain stem as well. This oscillation presumably causes both the periodicity of the alpha waves and the synchronous activation of literally millions of cortical neurons during each wave.

Front 23

23. Origin of delta waves

Back 23

Delta waves occur during deep SWS; this suggests that the cortex then is mainly released from the activating influences of the thalamus and other lower centers.

Front 24

24. Effect of varying levels of cerebral activity on the EEG frequencies

Back 24

During periods of mental activity the waves usually become asynchronous rather than synchronous, so that the voltage falls considerably, despite markedly increased cortical activity.

Front 25

25. Four stages of SWS

Back 25

Stage 1 is very light sleep, and the voltage of the EEG becomes very low. This is periodically broken by sleep spindles.

In stages 2, 3, and 4 of SWS, the frequency of the EEG becomes progressively slower until it reaches a frequency of only 1-3 Hz in stage 4; these are delta waves.

Front 26

26. REM sleep EEGs

Back 26

It is difficult to tell the difference between a brain in REM sleep and that of an active, awake person.

The waves are irregular and high frequency, which are normally suggestive of desynchronized nervous activity as found in the awake state.

Therefore, REM sleep is frequently called desynchronized sleep b/c there is lack of synchrony in the firing of the neurons, despite significant brain activity.

Front 27

27. What is epilepsy

What are the three types of epilepsy?

Back 27

Characterized by uncontrolled excessive activity of either part or all of the CNS.

Can be classified into 3 major types:
1. Grand mall
2. Petit mall
3. Focal

Front 28

28. Grand mal epilepsy

Back 28

Grand mal is characterized by extreme neuronal discharges in all areas of the brain - in the ce3rebrum, and even in the brain stem.

Also, discharges transmitted all the way into the spinal cord sometimes cause generalized tonic seizures of the entire body, followed toward the end of the attack by alternating tonic and spasmodic muscle contractions called tonic-clonic seizures.

Often the person bites or swallows his or her tongue and may have difficulty breathing. Also, signals transmitted from the brain from the viscera sometimes cause urination and defecation.

Front 29

29. Grand mal epilepsy #2

Back 29

The usual grand mal seizure lasts from a few seconds to 3-4 minutes. It is also characterized by postseizure depression of the entire nervous system; the person remains in stupor for 1 to many minutes after the seizure attack is over, and then often remains severely fatigued and asleep for hours thereafter.

The waves are high voltage, high-frequency discharges coming from all over the cortex.

Front 30

30. Areas activated in a grand mal seizure

Back 30

A grand mal attack involves not only abnormal activation of the thalamus and cerebral cortex cut also abnormal activation in the subthalamic brain stem portions of the brain activating system itself.

Front 31

31. What initiates a grand mal attack?

Back 31

1. Strong emotional stimuli
2. Alkalosis caused by overbreathing
3. Drugs
4. Fever
5. Loud noises or flashing lights

Front 32

32. What stops the grand mal attack?

Back 32

B/c of massive simultaneous activation of many reverberating neuronal pathways throughout the brain, neuronal fatigues probably stops the attack.

A second factor is probably active inhibition by inhibitory neurons that have been activated by the attack.

Front 33

33. Petit mal epilepsy

Back 33

Involves the thalamocortical brain activating system.

It is usually characterized by 3-30 seconds of unconsciousness or diminished consciousness during which time the person has twitch like contractions of muscles usually in the head region.

This is then followed by return of consciousness and resumption of the previous activities.

Front 34

34. Brain waves in petit mal seizures

Back 34

The brain wave pattern is typified by a spike and dome pattern.

The spike and dome can be recorded over most or all of the cerebral cortex, showing that the seizure involves much or most of the thalmocortical activating system of the brain.

Studies suggest that it results from oscillation of:
1. Inhibitory thalamic reticular neurons (GABA)
2. Excitatory thalamocortical and corticothalamic neurons

Front 35

35. Focal epilepsy

What are four causes of focal epilepsy?

Back 35

Can involve almost any local part of the brain, either localized regions of the cerebral cortex or deeper structures of both the cerebrum and brain stem.

Most often, focal epilepsy results from some localized organic lesion or functional abnormality such as:
1. Scar tissue in the brain that pulls on the adjacent neuronal tissue
2. A tumor that compresses an area of the brain
3. A destroyed area of brain tissue
4. Congenitally deranged local circuitry

Front 36

36. Mechanism of focal seizures

Back 36

Lesions can promote extremely rapid discharges in the local neurons; synchronous waves begin to spread over adjacent cortical regions.

These waves presumably result from localized reverberating circuits that gradually recruit adjacent areas fo teh cortex into the epileptic discharge zone.

Front 37

37. Focal seizures and Jacksonian epilepsy

Back 37

When such a wave of excitation spreads over the motor cortex, it causes progressive march of muscle contractions throughout the opposite side of teh body, beginning most characterstically in the mouth region and marching progressively downward to the legs but at other times marching in the opposite direction. This is called Jacksonian epilepsy.

Front 38

38. Psychomotor seizure

Back 38

A type of focal epilepsy which may cause:
1. A short period of amnesia
2. Attacks of abnormal rage
3. Sudden anxiety, discomfort, or fear
4. A moment of incoherent speed or mumbling of some trite phrase.

Attacks of this type freq involve part of the limbic portion of the brain, such as the hippocampus, the amygdala, the septum, and or portions of the temporal cortex.

Front 39

39. EEG waves during a psychomotor seizure

Back 39

EEG demonstrates low frequency, rectangular waves with a frequency between 2-4 Hz and with occasional superimposed 14 Hz waves.

Front 40

40. Possible cause of mental depression

Back 40

Diminished formation in the brain of norepinephrine or serotonin, or both.

About 70% of depressive patients can be treated effectively with drugs that increase the excitatory effects of norepinephrine and serotonin at nerve endings.

Front 41

41. Areas in the brain involved in serotonin and norepinephrine production

Back 41

Moderate numbers of norepinephrine secreting neurons are located int eh brain stem, especially in the local ceruleus. These neurons send fibers upward to most parts of the brain limbic system, thalamus, and cerebral cortex.

Also, many serotonin producing neurons located in the midline raphe nucleus of the lower pons and medulla send fibers to many areas of the limbic system and to some other areas of the brain.

Front 42

42. Current therapies for depression

Back 42

1. MAO inhibitors, which block destruction of norepinephrine and serotonin once they are formed.

2. Tricyclic antidepressants, which block reuptake of norepinephrine and serotonin by nerve endings so that these transmitters remain active for longer periods after secretion.

Front 43

43. Five possible causes of schizophrenia

Back 43

1. Multiple areas in the cerebral cortex prefrontal lobes in which neural signals have become blocked or where processing of the signals becomes dysfunctional b/c many synapses normally excited by the neurotransmitter glutamate lose their responsiveness.
2. Excessive excitement of a group of neurons that secrete dopamine in the behavioral centers of the brain, including in the frontal lobes
3. Abnormal function of a crucial part of the brain's limbic behavioral control system centered around the hippocampus
4. Too much dopamine
5. Reduced size of hippocampus

Front 44

44. Clinical features of Alzheimer's disease

Back 44

1. Amnesic type of memory impairment
2. Deterioration of language
3. Visuospatial deficits

Motor and sensory abnormalities, gait disturbances, and seizures are uncommon until the late phases of the disease.

Front 45

45. Causes of Alzheimer's

Back 45

Accumulation of beta-amyloid peptide in the brains. Excess beta-amyloid is the culprit here b/c:

1. All mutations in Alzheimer's disease produce an excess of beta-amyloid
2. Patients with trisomy 21 have three copies of the gene for amyloid precursor and develop neurological characteristics of Alzheimer's by middle life.
3. Patients who have an abnormality in apoE have accelerated deposition of amyloid and greatly increased risk for Alzheimer's .
4. Anti-amyloid antibodies in humans appears to attenuate the disease process.

Front 46

46. Definition of a seizure

Back 46

A seizure is an episode fo abnormally synchronized and high-frequency firing of neurons in the brain that results in abnormal behavior or experience of the individual.

A seizure is a symptoms of abnormal brain function.

Front 47

47. Definition of epilepsy

Back 47

Epilepsy is a disorder in whihc there is a tendency to have recurrent unprovoked seizures.

Epilepsy in a given individual can be caused by genetic, structural, metabolic, or other abnormalities, or the cause may be unknown.

Front 48

48. Ictal, interictal, and post--ictal

Back 48

Ictal means during a seizure, post ictal means immediately after a seizure, and interictal means between seizures.

Front 49

49. Partial seizures (focal, local)

Back 49

Abnormal paroxysmal electrical activity occurs in a localized region of the brain.

Front 50

50. Generalized seizures

Back 50

The abnormal electrical discharge involves the entire brain.

Note that a seizure can begin as a partial seizure and then spread to become secondarily generalized.

Front 51

51. Simple partial seizures

Back 51

Consciousness is spared. Partial seizures can have positive symptoms, such as hand twitching, or negative symptoms, such as impaired language abilities.

The manifestations of partial seizures depend on the anatomical regions of the brain in which the seizure activity occurs.

Typical duration for simple partial seizures is 5-10 seconds, although longer seizures are not uncommon. Often, there are no new post-ictal deficits.

Front 52

52. Aura

Back 52

Means "breeze". Auras are brief simple partial seizures of any type that are experienced by a patient with no outward behavioral manifestations.

They can occur in isolation, or they may serve as a warning for a larger seizure, when a patient has seizures that typically begin in one region of the brain before spreading.

Front 53

53. Complex partial seizures

Back 53

Simple partial onset followed by impairment of consciousness or impairment of consciousness at onset.

The impaired consciousness is due to seizure activity affecting wider regions of cortex, or deep brainstem and diencephalic regions.

Front 54

54. Most common locations for complex partial seizures

Back 54

The temporal lobes. However, such seizures can arise from the frontal, parietal, or occipital lobes as well.

Front 55

55. Automatisms

Back 55

Repetitive behaviors such as lip smacking, swallowing, or stereotyped hand or leg movements such as stroking, wringing, or patting.

Front 56

56. Duration of complex partial seizures

Back 56

1. 30 seconds to 1-2 minutes.

Post-ictal deficits may last from minutes to hours and can include unresponsiveness, confusion, amnesia, tiredness, agitation, aggression, and depression. Headache is common.

Front 57

57. What is the most common type of generalized seizure?

Back 57

A generalized tonic-clonic, or grand mal, seizure.

Typical duration is 30s to 2 minutes.

Immediately post-ictally, patients lie immobile, flaccid, and unresponsive with eyes closed, breathing deeply to compensate for the mixed metabolic and respiratory acidosis produced by the seizure. Post-ictal deficits last from minutes to hours and include profound tiredness, confusion, amnesia, headache, and other deficits related to the location of seizure onset.

Front 58

58. Phases of grand mal seizures

Back 58

A grand mal typically begins with a tonic phase characterized by loss of consciousness and generalized contraction of all muscles lasting for 10-15 seconds. This often results in stiff extension of the extremities, during which the patient may fall "like a tree" and injure themselves, and a characteristic expiratory gasp or moan may occur as air is forced past the closed glottis.

Next is the clonic phase, characterized by rhythmic bilateral jerking contractions of the extremities, usually in flexion, at a frequency of about 1 Hz, which gradually slow down and then stop.

Incontinence or tongue biting is common. There is usually a massive ictal autonomic outpouring with tachycardia, hypertension, hypersalivation, and pupillary dilation.

Front 59

59. Petit mal seizures (AKA absence seizures)

Back 59

These seizures are brief episodes of staring and unresponsiveness lasting for about 10s or less. There are not post-ictal deficits, except for a lack of awareness of what occurred during the brief time during the seizure.

These seizures are accompanied by a characteristic generalized 3-4 Hz spike and wave discharge on EEG recordings.

Front 60

60. How do absence seizures differ from grand mal?

Back 60

Although petit mal are generalized, they differ from grand mal seizures, which begin with a prolonged high-frequency electrical discharge that causes a more severe disruption of brain function.

Absence seizures are most common in childhood, and can occur multiple times per day. They can be provoked by hyperventilation, strobe lights, or sleep deprivation.

Front 61

61. Status epilepticus

Back 61

When seizures of any type occur continuously, or repeatedly in rapid succession, the condition is referred to as status epilepticus.

Generalized tonic-clonic status epilepticus is a medical emergency that required immediate and aggressive treatment.

Front 62

62. Response to a status epilepticus

Back 62

1. Administer anticonvulsants
2. Intubation and general anesthesia if anticonvulsants are ineffective
3. EEG recording
4. Blood tests
5. Head CT
6. Lumbar puncture (when appropriate)

Front 63

63. Dx of patients with epilepsy

Back 63

First step is to ascertain whether the episodes are epileptic seizures or another type of transient event. Epileptic seizures are usually brief events that are stereotyped from one episode to the next in a given patient.

If the events are epileptic seizures, the next step is to determine the type of seizure, as well as the localization if the seizures are focal in onset.

Finally, a cause for the seizures should be sought.

Front 64

64. What are the tools needed for a Dx in epilepsy?

Back 64

1. Detailed clinical history
2. Physical exam
3. Basic blood tests
4. MRI scan with special thin coronal cuts and pulse sequences used to view the medial temporal, cortical, and subcortical structures in detail
5. Interictal EEG.
-----------------
6. Continuous video and EEG monitoring
7. SPECT scan(Single photon emission CT)
8. PET scan
9. Neuropsychology testing

Front 65

65. Risk of new-onset seizures and age

Back 65

The risk of new-onset seizures is high in infancy and childhood, declines in adulthood, and then rises again in the elderly population.

Front 66

66. What are the most common causes of seizures in infancy and childhood?

Back 66

1. Febrile seizures
2. Congenital disorders
3. Perinatal injury

Front 67

67. What are the most common causes of seizures in patients over age 60?

Back 67

1. Cerebrovascular disease
2. Brain tumors
3. Neurodegenerative conditions

Front 68

68. Seizures and head trauma

Back 68

The risk of seizures after head trauma increases with the severity of the injury. Minor head injuries with no clear structural damage and only brief confusion or loss of consciousness (for less than 30 minutes) do not pose a significant risk for subsequent seizures.

Front 69

69. Blood chemistry and seizures

Back 69

Hypoglycemia, electrolyte abnormalities such as hyponatremia, hypernatremia, hypocalcemia, or hypomagnesemia; metabolic abnormalities or exposure to a variety of endogenous or exogenous toxic substances can provoke seizures.

Front 70

70. Febrile seizures (AKA simple febrile seizures)

Back 70

Febrile seizures are fairly common, occurring in 3-4% of all children, usually between the ages of 6 mos and 5 years.

These are usually brief, generalized tonic-clonic seizures called simple febrile seizures, which are not associated with increased risk of epilepsy.

Front 71

71. Complex febrile seizures

Back 71

These are defined as seizures lasting more than 15 minutes, or occurring more than once in 24 hours, or having focal features.

There is an increased risk of subsequent epilepsy in children with complex febrile seizures.

Front 72

72. Prolonged febrile seizures

Back 72

It has been hypothesized that prolonged febrile seizures cause subsequent temporal lobe epilepsy in some patients, through a pathologic process called mesial temporal sclerosis or hippocampal sclerosis, in which there is a marked neuronal loss and gliosis, particularly in the CA1 sector of the hippocampus.

Once established, there is often a latent period of up to several years between the precipitant and the onset of complex partial seizures.

Front 73

73. Treatment for mesial temporal sclerosis

Back 73

Once treated with anticonvulsant medications, seizures in patients with mesial temporal sclerosis rarely generalize. However, the complex partial seizures in these patients can be quite incapacitating, and are often associated with memory decline.

In addition, unlike the tonic-clonic seizures, the complex partial seizures in these patients are often medically refractory.

Unilateral surgical resection of the medial temporal lobe structures has a cure rate over 90% in patients with seizures localized to one temporal lobe.

Front 74

74. Rolandic epilepsy

Back 74

A common cause of focal, mostly nocturnal seizures in children that probably has autosomal dominant inheritance with incomplete penetrance. The EEG commonly shows characteristic centrotemporal spikes.

Onset is usually between ages 3 -13 and seizures are often mild, not always requiring medications.

Remission is nearly always complete by age 15.

Front 75

75. Familial primary generalized epilepsy syndromes

Back 75

Childhood absence epiplepsy (pyknolepsy)is characterized by typical absence seizures

This category also includes juvenile myoclonic epilepsy

Front 76

76. Treatment of epilepsy

Back 76

The basic goals of treatment are to reduce the risk of seizures while minimizing side effects, to achieve the best possible overall quality of life.

Major considerations include impact on driving, ability to work, public stigma, and effects of pregnancy and lactation.

Medications can be used to achieve satisfactory control of seizures in over 70% of cases.

Front 77

77. What are the first line agents for treatment of localization -related epilepsy, with or without secondary generalization?

Back 77

1. Cabamazepine (Tegretol)
2. Phenytoin (Dilantine)

Front 78

78. What are the seizure medications for childhood absence epilepsy?

Back 78

Ethosuximide (Zarontin)

If treatment with ethosuximide is unsuccessful, or if grand mal seizures are present as part of a primary generalized epilepsy syndrome, valproate (Depakote) is preferred.

Front 79

79. About how many patients with epilepsy have seizures that are medically refractory?

Back 79

About 20-30%.

Some children with refractory epilepsy may improve on a high-fat, low carbohydrate ketogenic diet, but the effect is often temporary and the diet is hard to maintain in the long term.

For unknown reasons, chronically implanted vagal nerve stimulators seem to reduce seizure frequency in some patients.

Front 80

80. Why would vagal nerve stimulators reduce seizure frequency?

Back 80

Vagal efferents reach the nucleus solitarius, and are relayed to the limbic system and other forebrain structures via the parabrachial nucleus of the pons.

Front 81

81. What is the ideal candidate for epilepsy surgery?

Back 81

In the ideal candidate, seizures always start in the same location, and this location can be safely resected without creating deficits.

The best surgical outcome stats are seen for patients with unilateral medial temporal lobe epilepsy, in which surgery controls seizures in 90% or more of cases.

Front 82

82. Angiogram Wada test

Back 82

In this test the sedative agent sodium amytal is injected through an angiographic catheter directly into each common carotid artery, causing transient inhibition of the injected hemisphere for approximately 10 minutes.

After each injection, languages is tested, and the presence or absence of aphasia is used to localize which hemisphere is dominant for language so that language areas can be avoided during surgery.

Front 83

83. Memory tests in patients with normal bilateral medial temporal memory function

Back 83

Injection of one hemisphere with sodium amytal does not eliminate memory, since the other hemisphere can compensate.

Front 84

84. Memory tests in patients with abnormal bilateral medial temporal memory function

Back 84

Often the case in patients with medial temporal epilepsy, injection of the contralateral hemisphere causes severe memory difficulties.

Preserved memory with injection of the hemisphere ipsilateral to seizure onset is reassuring b/c it suggest that the contralateral hemisphere will be able to support memory function after the ipsilateral medial temporal structures are resected.

Front 85

85. Vascular supply to the medial temporal structures

Back 85

In the Wada test, amytal is injected into the common carotid artery, which in most individuals perfuses the ACA and MCA territories, but not the PCA territory.

Since the medial temporal lobe structures are perfused by the PCA, it is not immediately obvious why the Wada test should inhibit medial temporal function.

Front 86

86. In the Wada test, how does the injection inhibit the medial temporal function if it is injected into the ACA/MCA areas?

Back 86

The most likely explanation is that the large ACA/MCA injection inhibits most of the hemispheric cortex, white matter, and corpus callosum, thereby indirectly inhibiting the medial temporal lobe by cutting off its major sources of input.

Front 87

87. Multiple subpial transection

Back 87

In some patients, the region of seizure onset lies in a functionally critical area such as the motor or language cortex, and surgical resection cannot safely be performed.

In these patients a multiple subpial transection may be helpful. In this procedure, a special sharpened probe is inserted under the pia and is used to sever the cortical-cortical connections, thereby making multiple parallel tracts that functionally disconnect the epileptogenic cortex.

Front 88

88. Callosotomy

Back 88

Patients with severe epilepsy arising from multiple locations in the brain may benefit from callosotomy.

In this procedure, the corpus callosum is cut, preventing seizures from propagating from one hemisphere to the other.

This procedure does not cure seizures; it is reserved mainly for patients who have frequent falls and injuries when their seizures generalize.

Front 89

89. Hemispherectomy

Back 89

In some patients, the seizure onset is not localized to a specific region but rather to multiple regions within a single hemisphere.

In patients younger than 2-3 years, hemispheric specialization is still under development. Therefore, in some of these patients, hemispherectomy can be considered.

Remarkably, many patients do quite well following this procedure and are able to lead functional lives. Seizures are often cured, allowing language and motor development to proceed, with language and motor representations for both sides of the body forming in the single remaining hemisphere.

Front 90

90. Clinical features of medial temporal lobe seizures

Back 90

An indescribable sensation, rising epigastrium (butterflies in the stomach), nausea, deja vu, fear, panic, unpleasant odor, autonomic phenomena (tachycardia, pupillary dilation, piloerection, borboyrgmi, belching, pallor, flushing), bland staring with unresponsiveness, oroalimentary automatisms (lip smacking, chewing, swallowing), bilateral or unilateral gestural automatisms, contralateral dystonia with ipsilateral automatisms.

Front 91

91. Clinical features of lateral temporal lobe seizures

Back 91

Vertigo, inability to hear, simple auditory hallucinations (buzzing, roaring engine, tones), elaborate auditory hallucinations (voices, music). Aphasia, including inability to understand what people are saying, is more common with dominant temporal seizures. Saying words or phrases repeatedly and having musical hallucinations are more common with nondominant temporal seizures.

Front 92

92. Misc features of temporal lobe seizures

Back 92

Usual duration of 1-2 minutes, often with post-ictal amnesia, tiredness, headache, emotional changes, or other focal deficits.

Most common cause of complex partial seizures. Head or eye deviation probably results from spread to frontal or parietal lobes.

Medial temporal lobe seizures associated with hippocampal sclerosis usually do not generalize once treated with meds, however, the complex partial seizures in this condition are often medically refractory and freq can be cured by surgery.

Front 93

93. Clinical features of dorsolateral convexity frontal lobe seizures

Back 93

Dorsolateral convexity frontal lobe seizures:

Contralateral tonic or clonic activity (primary motor cortex); strong version (turning) or the eyes, head and body away from side of the seizure (prefrontal cortex and frontal eye fields). Aphasia (dominant hemisphere)

Front 94

94. Clinical features of supplementary motor area frontal lobe seizures

Back 94

Supplementary motor area frontal lobe seizures:

Fencing posture with extension of contralateral upper extremity, other tonic postures, speech arrest, unusual sounds.

Front 95

95. Clinical features of orbitofrontal and cingulate frontal lobe seizures

Back 95

Orbitofrontal and cingulate frontal lobe seizures:

Elaborate motor automatisms, making unusual sounds, autonomic changes, olfactory hallucinations (orbitofrontal), incontinence (cingulate).

Front 96

96. Misc comments about frontal lobe seizures

Back 96

Frontal lobe seizures are often brief, occur multiple times per day, and may have no post-ictal deficits. Nocturnal exacerbation is common.

Elaborate motor automatisms without loss of consciousness or postictal deficits often lead to misdiagnosis as psychogenic episodes.

Front 97

97. Clinical features of parietal lobe seizures

Back 97

Parietal lobe seizures:

Vertigo, contralateral numbness, tingling, burning, senssation of movement or need to move, aphasia (dominant hemisphere).

Eyes and head may deviate toward or away from the side of the seizure.

Front 98

98. Clinical features or occipital lobe seizures

Back 98

Occipital lobe seizures:

Sparkles, flashes, pulsating colored lights, scotoma, or hemianopia in contralateral visual field (primary visual cortex), formed visual hallucinations (inferior temporo-occipital association cortex), nystagmoid or oculogyric jerks, palpebral jerks, eye blinking, sensations of eye oscillation.

Front 99

99. Misc comments about occipital lobe seizures

Back 99

Occipital lobe seizures may be precipitated by changes in lighting conditions.

Often associated with migraine-like symptoms.

Variable spread to other lobes is common and can lead to mislocation.

Front 100

100. Cancer basics (7)

Back 100

1. A class of disorders showing uncontrolled cell proliferation
2. Disease of cellular differentiation
3. Normal growth and differentiation disrupted
4. Different degrees of tumor, different stages
5. May reflect degree of genetic change
6. Carcinogenesis is a multi-step process
7. Both genes and environment are important

Front 101

101. Neoplasm, tumor, tumorigenesis

Back 101

Uncontrolled cell growth leads to a mass of cells termed a neoplasm, or tumor.

The formation of tumor is called tumorigenesis.

Front 102

102. Apoptosis, angiogenesis

Back 102

Cancer cells must disable the process of programmed cell death (apoptosis).

The growing cell mass requires nourishment, so a new blood supply must be obtained through angiogenesis.

Front 103

103. Malignant, metastasize, benign

Back 103

Additional inhibitory signals must be overcome for the tumor to achieve a malignant state, in which neoplasms invade nearby tissues and metastasize (spread) to more distant sites in the body.

The capacity to invade and metastasize distinguishes malignant from benign neoplasms.

Front 104

104. Carcinoma, sarcoma, lymphoma, glioma, leukemia

Back 104

Major types of tumors include those of epithelial tissue (carcinomas, the most common tumors), connective tissue (sarcomas), lymphatic tissue (lymphomas), glial cells of the CNS (gliomas), and hematopoietic organs (leukemias).

Front 105

105. Monoclonal

Back 105

The cells composing a tumor are usually derived from a single ancestral cell, making them a single clone (monoclonal).

Front 106

106. Two main causes of cancer

Back 106

1. Genetic
2. Environmental

Front 107

107. Genetic causes of cancer

Back 107

1. Changes occur in genes that regulate proliferation
2. May be caused by mutagenic agents
-these are carcinogens
3. If not in germline, it will not be inherited (even though they are genetic events, they are not inherited).

Front 108

108. Environmental causes of cancer

Back 108

1. Carcinogens can be environmental
2. Cancer frequencies change with environment
3. US vs. Japan, colon vs. stomach cancer

Front 109

109. The regulation of cell growth is accomplished by what four things?

Back 109

1. Growth factors and receptors
2. Specific receptors for growth factors
3. Signal transduction pathways
4. Nuclear transcription factors

Front 110

110. What are the major features of cellular regulation?

Give an example.

Back 110

External growth factors (proteins and steroid hormones such as epidermal growth factor) bind to membrane-spanning growth factor receptors on the cell surface, activating signal transduction pathways in which genes such as RAS participate.

Components of the signal transduction pathway in turn interact with nuclear transcription factors, such as MYC and FOS, which can bind to regulatory regions in DNA.

Front 111

111. Multi-hit concept of carcinogenesis

Back 111

Mutations mayoccur in any of the steps involved in regulation of cell growth and differentiation.

Accumulation of such mutations within a cell lineage may result in a progressive deregulation of growth, eventually producing a tumor cell.

An example of this concept is given by colorectal cancer, in which several genetic events are required to complete the progression from a benign growth to a malignant neoplasm.

Front 112

112. Inherited cancer

Back 112

1. Defects in certain classes of genes are important
2. Mutations can occur in germlines
3. These mutations can be inherited by subsequent generations
4. These inherited genes predispose to cancer
5. All cells have the mutant gene
6. All cells have taken one step on the pathway to cancer

Front 113

113. Cancer in families

Back 113

1. You inherit a predisposition, not a disease
2. Many factors are important
3. Better screen discovers more cases

Front 114

114. Knudson's two-hit model

Back 114

1. Retinoblastoma has two types:
-Bilateral, runs in families
-Unilateral, appears sporadically
2. Only a few retinoblasts progress to tumors
3. Need two mutations for cancer
4. One copy is bad already in inherited form
5. Probability is high that a few cells will mutate
6. Sporadic requires two events in one cell

Knudson reasoned that at least two mutations may be required to create a retinoblastoma.

One of the mutations would alter the retinoblastoma gene; the second would be an additional unspecified genetic event occurring in an already altered cell.

Front 115

115. Why is Knudson's two-hit model significant?

Back 115

The hypothesis of a second event was required to explain why only a tiny fraction of the retinoblasts of an individual who has inherited a mutant retinoblastoma gene actually give rise to tumors.

Front 116

116. What is a constitutional mutation?

Back 116

A mutation present in all cells of the body.

Front 117

117. What are the three major classes of cancer genes?

Back 117

1. Tumor suppressor genes
-normally control cell cycle and proliferation
-Rb1, CDK inhibitors

2. Oncogenes
-Enhance cell proliferation when activated
-Few inherited mutations

3. DNA repair genes
-help maintain integrity of genome
-BRCA1, BRCA2, mismatch repair genes

Front 118

118. What is the inheritance paradox?

Back 118

1. Mutations appear to be dominant
-inheritance pattern in pedigrees

2. Are recessive at cellular level
-require second copy to be mutated

3. Oncogenes are rarely seen in inherited forms
-mainly dominant gain-of-function mutations

4. Truly dominant forms might preclude normal development, and be lethal.

Front 119

119. Tumor suppressor genes

Back 119

The disovery tha retinoblastoma resutls when both allels of the same locus on chromosome 13 are inactivated in the same retinoblast led to the concept of tumor suppression genes.

The products of such genes suppress tumor formation by controlling cell growth and can do so even if a cell contains only one normal version of the gene.

Loss-of-function mutations that inactivate both copies of a cell's tumor suppressor gene can lead to uncontrolled cellular proliferation.

Front 120

120. Proto-oncogenes

Back 120

Proto-oncogenes encode products that control cell growth and differentiation.

Front 121

121. Oncogenes

Back 121

When proto-oncogenes become mutates, they may become oncogenes, which can cause cancer. Most oncogenes act as dominant gain-of-function mutations that lead to the deregulation of cell cycle control.

In contrast to tumor suppressor genes, most oncogenes do not exhibit germline mutations that cause inherited cancer syndromes.

Instead, somatic mutations are seen that lead to sporadic cancers.

Front 122

122. Retrovirus

Back 122

Retroviruses are a type of RNA virus that is capable of using reverse transcriptase to transcribe RNA into DNA. In this way, the RNA genome of the retrovirus is converted to DNA, which can be inserted into a chromosome of a host cell.

Front 123

123. Transfection experiments

Back 123

The identification of cellular genes involved in carcinogenesis was complemented by experiments in which mutated forms of cellular proto-oncogenes were transferred from tumor cells to nontumor cells (transfection) causing transformation of the recipients.

This helps to confirm the role of oncogenes in carcinogenesis.

Front 124

124. RAS

Back 124

Rat sarcoma oncogenes - the characterization of the protein product of mutant forms of RAS has revealed an important mechanism for the regulation of signal transduction.

The RAS protein normally cycles between an active form bound to GTP and an inactive form bound to GDP.

The biochemical sequence of RAS mutations is a RAS protein that is unable to shift from the active GTP form, which stimulates growth, to the inactive GDP form. The mutant RAS protein cannot quench its growth signal.

Front 125

125. Mapping in tumors

Back 125

1. Standard and special methods can be used.
2. Loss of a second copy leads to new methods.
3. May be due to deletion or rearrangement.
4. Tumor cells compared to normal cells.
5. Look for areas of consistent change.
6. Heterozygous loci studied.
7. Lost markers indicate loss of heterozygosity near gene of interest.

Front 126

126. Genetic cause of chronic myelogenous leukemia

Back 126

Involves the Philadelphia chromosome, in which a translocation between chromosomes 9 and 22 activates the ABL proto-oncogene and produces chronic myelogenous leukemia.

The translocation fuses two genes together: the retinoic acid receptor alpha (RARα) gene on chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15.

The fusion product (PML-RARα) interferes with the ability of the normal RARα protein to induce terminal differentiation of myeloid cell.

The fusion product also impairs the function of the PML protein, which acts as a tumor suppressor by helping to initiate apoptosis in damaged cells.

Front 127

127. Genomic instability

Back 127

Tumor cells typically are characterized by widespread mutations, chromosome breaks, and aneuploidy.

This condition, termed genomic instability, contributes to tumorigenesis b/c mutations and chromosome defects can activate oncogenes or deactivate tumor suppressor genes.

Genomic instability can occur b/c of defects in the proteins required for accurate cell division or in proteins responsible for DNA repair.

These defects are in turn the result of mutations.

Front 128

128. DNA mismatch repair

Back 128

Some cancers can result from faulty DNA mismatch repair (so named b/c single-base mutations can lead to a DNA molecule in which base pairs are not complementary to one another: a "mismatch")

Front 129

129. What are some diseases caused by faulty DNA mismatch repair?

Back 129

1. Some breast cancers
2. Inherited form of colon cancer
3. Xeroderma pigmentosum - multiple skin tumors

Front 130

130. Senescence

Back 130

Even after a tumor cell has escaped regulation by tumor suppressors or DNA repair proteins, it must overcome one more hurdle to unlimited proliferation: the intrinsic limitation on the number of cell divisions allowed to each cell.

A cell is restricted to about 50-70 mitotic division. After reaching this number, the cell typically becomes senescent and cannot continue to divide.

Front 131

131. Telomerase

Back 131

Tumor cells overcome the senescence by activating a gene that encodes telomerase, a reverse transcriptase that replaces the telomeric segments that are normally lost during cell division.

This activation is part of a process that allows a tumor cell to continue to divide without the restraint ordinarily imposed by telomere shortening.

Front 132

132. What are the two avenues for initial mapping of tumor genes?

Back 132

1. The primary and most general route is through linkage mapping in families, where the pattern of inheritance of the cancer phenotype defines the genetic transmission of an altered allele. The chromosomal segment bearing this mutation can be identified by linkage with polymorphic markers.

2. The second basis for mapping takes advantage of the frequent chromosomal losses associated with revealed tumor suppressor genes. Observation that a specific chromosome segment is deleted in a tumor suggests a map location for the inherited mutation. In other words, by showing that one homolog of a chromosome is missing in DNA from a tumor.

Front 133

133. NF1 gene identification

Back 133

The initial evidence for mapping of the neurofibromatosis type 1 gene (NF1) to chromosome 17 came from linkage studies in families.

There are two different translocations in region 17q that were only 50 kb apart. These translocations were assumed to have caused neurofibromatosis in these individuals be disrupting the NF1 gene.

The breakpoints provided the physical clues necessary to define several candidate genes that were screened for mutations in patients with NF1.

Front 134

134. NF1 and GAP

Back 134

The nucleotide sequence of the NF1 gene provided an early clue to function when its predicted AA sequence was compared with AA sequences of known gene products.

Extended similarities were observed with the mammalian GTPase-activating protein (GAP). This was an important finding, b/c at least one function of GAP is to decrease the amount of active, GTP-bound RAS.

Front 135

135. GTP-bound RAS

Back 135

The RAS protein is a key component of the signal transduction pathway, transmitting positive growth signals in its active form.

The closely associated NF1 gene product, neurofibromin, also plays a role in signal transduction by down-regulating RAS.

Front 136

136. Why would a mutation in one NF1 allele contribute to the development of neurofibromatosis?

Back 136

Reduced expression of the NF1 gene permits increased RAS activity and allows the cell to escape from differentiation and continue its growth.

Loss of the remaining allele further encourages unchecked growth.

Front 137

137. TP53 gene

Back 137

Somatic mutations in the TP53 gene are found in more than half of all human tumors, making this the most commonly altered cancer gene. Mutations in the TP53 gene occur in more than 50 different types of tumors, including those of the bladder, brain, breast, cervix, colon, esophagus, larynx, liver, lung, ovary, pancreas, prostate, stomach, skin, and thyroid.

Front 138

138. Approximately 80-90% of TP53 mutations are of what type?

Back 138

80-90% are of the missense type, and these are concentrated int he portion of the gene that encodes a DNA-binding domain.

Front 139

139. Function of TP53

Back 139

Like RB1, and NF1, TP53 is a tumor suppressor gene. It protein product, p53, increases in quantity in response to cell damage.

Acting as a transcription factor, p53 can interact with many other genes that help to control the cell cycle.

Front 140

140. Example of p53 function

Back 140

p53 binds to the promoter of CDKN1A, whose protein produce, p21, is a CDK inhibitor that blocks CDK4's inactivation of pRb.

This halts the cell cycle in the G1 phase, before DNA replication occurs in S phase.

Arrest of the cell cycle before S phase provides time for the repair of damaged DNA. If the cell's DNA is severely damaged, p53 may instead induce apoptosis.

Front 141

141. What occurs when TP53 is mutated?

Back 141

When TP53 is mutated, cells with damaged DNA may evade both repair and destruction, and continued replication of the damaged DNA may lead to tumor formation.

Front 142

142. What carcinogenic substances can induce specific TP53 mutations?

Back 142

For example, dietary ingestion of aflatoxin B1, which can produce liver cancer, is associated with a mutation that produces an arginine-to-serine substitution @ position 249 of the p53 protein.

Exposure to benzopyrene, a powerful mutagen and carcinogen found in cigarette smoke, leads to alterations of specific TP53 base pairs in lung tumors.

Front 143

143. Li-Fraumeni syndrome (LFS)

Back 143

Germline mutations in TP53 are responsible for an inherited cancer condition known as the Li-Fraumeni syndrome (LFS).

This rare syndrome is transmitted in autosomal dominant fashion and inovles breast and colon carninomas, soft-tissue sarcomas, osteosarcomas, brain tumors, leukemia, and adrenocortical carcinomas.

These tumors usually develop at early ages in members of LFS families, and multiple primary tumors are commonly seen in an affected individual.

Front 144

144. TP53 mutations and risk of cancer

Back 144

As in retinoblastoma, the inheritance of a mutated TP53 gene greatly increases the individual's susceptibility to subsequent cell transformation and tumor development when a cell loses the other, normal copy of TP53 (two hit model).

LFS family members who inherit an abnormal TP53 gene, approximately 50% will develop invasive cancer by 30 years and more than 90% will develop invasive cancer by 70.

Front 145

145. What mutations account for LFS cases?

Back 145

TP53 mutations account for 75% of LFS cases.

Some of the remaining cases are the result of mutations in another tumor suppressor gene, CHK2. This gene encodes a kinase that normally phosphorylates p53 in response to ionizing radiation, resulting in the accumulation and activation of p53.

Loss-of-function mutations in CHK2 result in a lack of p53 activation, causing LFS via the p53 pathway.

Front 146

146. In what two ways is TP53 medically important?

Back 146

1. The presence of TP53 mutations in tumors, particularly those of the breast and colon, often signals a more aggressive cancer with relatively poor survival prospects. It is thus a useful prognostic indicator.

2. TP53 may ultimately prove important in tumor prevention. Lab experiments show that the insertion of a normal TP53 gene into tumor cells can induce tumor regression by inducing abnormal cancer cells to undergo apoptosis.

Front 147

147. Familial adenomatous polyposis (FAP)

Back 147

FAP is characterized by the early appearance of multiple adenomas, or polyps, of the colon. Colonic adenomas are now understood to be the immediate precursors to colon cancer.

The multiple adenomas of the patient with FAP therefore present a grave risk of early malignancy. Early detection and removal of adenomatous polyps can significantly reduce the occurrence of colon cancer.

Front 148

148. The familial adenomatous polyposis gene, APC

Back 148

The gene responsible for FAP was initially placed on the map of the long arm of chromosome 5 by linkage analysis in families after a microscopically visible chromosomal deltion in a patient with this syndrome provided an important clue to its location.

Discovery of small, overlapping deletions in two unrelated patients provided the key to isolation of the gene. Among the genes that lay within the 100-kb region that was deleted in both patients, one showed apparent mutations in other patients. This mutation was seen in one patient but not in his unaffected parents, confirming the identification of the APC gene.

Front 149

149. APC gene

Back 149

Like RB1 and TP53, APC is a tumor suppressor gene, and both copies of APC must be inactivated for tumor progression to begin. Individuals who inherit an APC mutation typically experience somatic loss-of-function mutations in hundreds of their colonic epithelial cells, giving rise to multipe adenomas.

In some cases, loss of function of APC occurs b/c of hypermethylation of APC's promoter region, which results in reduced transcription.

Front 150

150. APC gene #2

Back 150

APC gene mutated in 85% of sporadic cases.

APC mutation/loss is not sufficient by themselves for cancer progression.

Other genes may also need to be altered.

Early step, others necessary

Multi-step model of tumor progression

Front 151

151. KRAS tumors

Back 151

Mutations are seen in the KRAS gene in approx 50% of colon tumors. This gene encodes a signal transduction molecule and a gain of function mutation increases signaling and thus cellular proliferation.

Front 152

152. Multi-step model of tumor progression

Back 152

1. First hit is APC mutation
-down-regulates ß-catenin, MYC signal transduction
-cause proliferation, early adenoma

2. K-RAS activation may follow (50%)
-gain of function, signal transduction pathway

3. TP53 mutations common later
-over 50% of tumors, in adenocarcinomas

4. Other genes may be altered
-SMAD4, genes leading to metastasis

Front 153

153. What are the three ways in which the APC protein acts as a tumor suppresor?

Back 153

1. It down regulates ß-catenin, a key molecule in the Wnt signal transduction pathway. Among other things, this pathway is involved in activation of the MYC transcription factor. By reducing ß-catenin levels, APC dampens signals that lead to cellular proliferation.

2. Some APC genes have gain of function mutations in the ß-catenin gene, thus confirming the potential etiological role of this gene in colon cancer.

3. APC mutations are also thought to affect cell-cell and cell-matrix adhesion properties. Again, this activity is mediated through ß-catenin, which interacts with a cell surface molecule (E-cadherin) whose loss of function leads to abnormal cell adhesion properties.

4. APC is expressed int eh microtubules that pull chromosomes apart during meiosis. Alterations in APC result in altered microtubule activity such that aneuploidies and chromosome breaks arise during mitosis.

Front 154

154. Hereditary nonpolyposis colon cancer

Back 154

Hereditary nonpolyposis colon cancer (HNPCC), a second form of inherited colon cancer, amounts for approx 1-5% of all colorectal cancer cases.

Like FAP, HNPCC is an autosomal dominant, high penetrance cancer syndrome, with a lifetime colorectal cancer risk of 70% to 90% in heterozygotes. In addition, endometrial cancer occurs in approx 20-40% of female mutation carriers.

Cancers of the small bowel, renal pelvis, ovary, and ureter are seen in a smaller proportion of gene carriers.

Front 155

155. Mutations in what gene account for approx 40-60% of HNPCC cases?

Mutations in what other gene accounts for the rest?

Back 155

Mutations in the MSH2 gene accoutn for approximately 40-60% of HNPCC cases, and mutations in the MLH1 gene account for about 25-30% of cases.

Mutations in four other genes PMS1, PMS2, MLH3, and MSH6, help to account for the small proportion fo additional cases.

Each of these genes is known to play an important role in DNA mismatch repair). Inactivation of both alleles of any one of these genes increases the genome-wide mutation rate in an affected cell by as much as 1,000 fold.

Front 156

156. Increased rate of mutation in the HNPCC cases results in what?

Back 156

This increased rate of mutation results in the alteration of a number of cellular regulatory genes, thus leading to an increased frequency of cancer.

A characteristic feature of tumors from HNPCC patients is a high degree of instability of microsatellite loci, which generates many new microsatellite alleles.

Front 157

157. What is microsatellite instability associated with?

Back 157

Such microsatellite instability is seen in about 15% of sporadic colorectal carcinomas, but somatic loss-of-function mutations in the HNPCC genes seem to occur only infrequently in these tumors.

Instead, the most common alteration seen in these sporadic tumors is hypermethylation of the MLH1 gene, resulting in its inactivation.

Front 158

158. Comparison of FAP and HNPCC

Back 158

In FAP, an inherited APC mutation results in a large number of polyps, each of which has a relatively low probability of incurring all of the other genetic alterations required for progression to metastatic cancer.

But, b/c the number of polyps is large, there is a high probability (almost 100%) that at least one of them will produce a cancerous tumor by age 45.

In HNPCC, the number of polyps is much smaller, but, b/c of a lack of DNA repair, each polyp has a relatively high probability of experiencing the multiple alterations necessary for tumor development. Consequently, the average age of onset of colon cancer in HNPCC is similar to that of FAP.

Front 159

159. Inherited breast cancer

Back 159

Two genes, BRCA1 and BRCA2, have been identified as major contributors to inherited breast cancer.

Front 160

160. What proportion of breast cancer cases are the result of BRCA1 and BRCA2 mutations?

Back 160

Most population based studies show that only a small percentage of all breast CAs - approx 1-3% can be attributed to inherited mutations in BRCA1 or BRCA2.

Among women with breast CA who also have a positive family history of the disease, the percentage with inherited mutations increases to 20%.

Among affected women who have a positive family history of breast and ovarian cancer, 60-80% have inherited mutations.

Front 161

161. Women who inherit a mutation in BRCA1 or BRCA2 experience what lifetime risk in developing breast cancer?

Ovarian cancer? Other cancers?

Back 161

A 50-80% lifetime risk of developing breast cancer.

BRCA1 mutations also increase the risk of ovarian cancer among women (20-50%) and they confer a modestly increased risk of prostate and colon cancers.

Front 162

162. What about BRCA2 mutations?

Back 162

BRCA2 mutations are associated with an increased risk of ovarian cancer (10-20% lifetime risk).

Approx 6% of males who inherit a BRCA2 mutation will develop breast cancer; this represents a 100x increase over the risk in the general male population.

Front 163

163. How were BRCA1 and BRCA2 identified?

Back 163

Both identified by linkage analysis in families, followed by positional cloning. Both genes are large. More than 650 BRCA1 mutations and more than 400 BRCA2 mutations have been identified.

Front 164

164. What are most of the mutations in BRCA1 and BRCA2?

Back 164

Most of these mutations result in truncated protein products and a consequent loss of function.

Front 165

165. Does BRCA1/2 mutations follow a two-hit or multi-hit model?

Back 165

As for the RB1 and APC genes, affected individuals inherit one copy of a BRCA1/2 mutation and then experience a somatic loss of the remaining normal allele in one or more cells. This follows the two hit model.

In contrast to RB1 and APC, somatic mutations affecting these genes are seldom seen in sporadic (noninherited) breast CA.

Front 166

166. How are BRCA1 and BRCA2 genes similar?

Back 166

Although BRCA1 and BRCA2 share no significant DNA sequence similarity, they both participate in the DNA repair process.

Both genes thus participate in an important DNA repair pathway, and their inactivation results in incorrect DNA repair and genomic instability.

In addition to their roles in the RAD51 pathway, BRCA1 and BRCA2 help to suppress tumor formation through their interactions with proteins such as p53, pRb, and Myc.

Front 167

167. Protein product of BRCA1 - what is its role?

Back 167

The protein product of BRCA1 is phosphorylated and thus activated by the ATM and CHK2 kinases in response to DNA damage.

The BRCA1 protein product binds to the BRCA2 product, which in turn binds to RAD51, a protein complex involved in the repair of double stranded DNA breaks.

Front 168

168. Mutations in CHK2 cause...?

Back 168

LFS

Front 169

169. Mutations in the ATM gene cause...?

Back 169

Ataxia telangiectasia, an autosomal recessive disease the involves extensive genomic instability, cerebellar ataxia, dilated vessels in the eyes and skin (telangiectasia), and cancers of mainly lymphoid origin.

Front 170

170. Fanconi anemia

Back 170

Another autosomal recessive chromosome instability syndrome, Fanconi anemia, can be caused by the inheritance of two copies of a BRCA2 mutation.

Front 171

171. What other inherited mutations can cause breast CA?

Back 171

Mutations in several other tumor suppression genes can cause breast CA, such as CHK2, and TP53 genes.

Germline mutations in a tumor suppressor gene called PTEN are responsible for Cowden disease, which is characterized by multiple benign tumors and an increased susceptibility to breast cancer.

Some studies have suggested that heterozygous carriers of mutations in the ATM gene have an increased susceptibility to breast CA.

Front 172

172. Familial melanoma

What gene is responsible?

Back 172

It is estimated that approx 5-10% of melanoma cases occur in inherited, familiar forms.

Linkage analysis in families and studies of loss of heterozygosity in melanoma to the short arm of chromosome 9.

Subsequent positional cloning and mutation analysis led to the identification of the CDKN2A gene as a cause of familial melanoma.

Front 173

173. CDKN2A

Back 173

This gene encodes a CDK inhibitor (p16) which, like p21, interacts negatively with CDK4 that phosphorylates and down-regulates the pRb protein.

B/c active pRb acts as a brake on the cell cycle, loss-of-function mutations in the CDKN2A tumor suppressor gene result in a lack of cell cycle control, thereby producing melanomas.

Front 174

174. What else can cause familial melanoma?

Back 174

Inherited mutations in the gene that encodes CDK4 can also result in familial melanoma.

These gain of function mutations convert the CDK from a proto-oncogene to an activated oncogene.

The activated CDK4 constantly down-regulates pRb, resulting again in a lack of cell cycle control and tumor formation.

Front 175

175. What is significant about melanoma?

Back 175

Melanoma provides an example in which the same tumor type can result from either the activation of a proto-oncogene (CDK4) or the loss of a tumor suppressor gene (CDKN2A).

Front 176

176. What else does CDKN2A play a role in?

Back 176

CDKN2A plays a role not only in familial melanoma but also in approx 25% of sporadic melanomas, in which somatic loss-of-function mutations of this gene lead to inactivation of the p16 tumor suppressor protein.

Approx 2/3's of these tumors contain gain-of-function mutations in BRAF, a gene that encodes a kinase involved in the RAS signal transduction pathway. In addition, loss of function mutations in the APAF1 gene enable the altered cell to avoid the p53 apoptosis pathway.

Front 177

177. The RET gene

Back 177

The RET gene encodes a receptor tyrosine kinase that includes an extracellular receptor domain, a transmembrane domain, and an intracellular tyrosine kinase domain.

RET is involved in embryonic neural crest cell migration, and it is normally activated by a complex consisting of glial-derived neurotrophic factor (BDNF) and a coreceptor termed GFRα.

The RET protein interacts with several signal transduction pathways, including the well known RAS pathway.

Front 178

178. Inherited loss of function mutations in RET are associated with...?

Back 178

Hirschsprung disease (congenital megacolon)

Front 179

179. Inherited gain of function mutations in RET are associated with...?

Back 179

Any of three forms of inherited multiple endocrine neoplasia type 2 (MEN2):

1. MEN2A
2. MEN2B
3. Mutations in both the extracellular and tyrosine kinase domains of RET

Front 180

180. MEN2A

Back 180

MEN2A: characterized by medullary thyroid carcinomas, PTH hyperplasia, and pheochromocytoma (adrenal tumor)..

More than 98% of MEN2A cases are caused by missense mutations that affect cysteine residues in RET's extracellular domain.

Front 181

181. MEN2B

Back 181

MEN2B: similar to MEN2A but lacks PTH hyperplasia and includes multiple mucosal neuromas and a marfanoid appearance.

Nearly all MEN2B alterations are missense mutations that affect RET's tyrosine kinase domain.

Front 182

182. Dx and treatment of MEN2A and MEN2B

Back 182

Prophylactic thyroidectomy before 6 years of age is recommended for children who inherit a disease causing mutation (thyroidectomy before age 3 may be indicated for the more aggressive MEN2B tumors).

Front 183

183. RET gene summary

Back 183

The RET gene provides an example of extraordinary allelic heterogeneity.

Loss-of-function mutations in this gene produce defects in the embryonic development of the bowel, while gain-of-function mutations result in increased signal transduction and various forms of endocrine neoplasia.

Front 184

184. What are the three criteria that was established for distinguishing transformed cells from normal cells in culture?

Back 184

1. The requirement for serum in the cell culture medium to stimulate cell growth

2. The ability to grow without attachment to a supporting matrix (anchorage dependence)

3. Ability of cells to form tumors when they are injected into mice that lack an immune system

Front 185

185. Chemical and physical alterations in DNA

Back 185

An alteration in the chemical structure of DNA, or of the sequence of bases in a gene, is an absolute requirement for the development of cancer.

Can occur via carcinogens, chemotherapeutic agents, radiation, UV light.

Each chemical carcinogen or reactant creates a characteristic modification in a DNA base. The DNA damage, if not repaired, introduces a mutation into the next generation when the cell proliferates.

Front 186

186. Carcinogens

Back 186

Chemical carcinogens found in the environment and ingested in foods are generally stable lipophilic compounds that must be activated by metabolism in the body to react with DNA.

Front 187

187. UV radiation

Back 187

Structural alterations in DNA also occur through radiation and through UV light, which causes the formation of pyrimidine dimers. More than 90% of skin cancers occur in sunlight exposed areas.

UV rays derived from the sun induce an increased incidence of all skin cancers, including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma of the skin.

Front 188

188. What wavelength of UV light is most associated with skin CA?

Back 188

UVB - (280-320 nm), it forms pyrimidine dimers in DNA.

This type of DNA damage is repaired by nucleotide excision repair aptwhays that require products of at least 20 genes.

With excessive exposure to the sun, the nucleotide excision repair pathway is overwhelmed, and some damage remains unrepaired.

Front 189

189. Proto-oncogenes and oncogenes

Back 189

Proto-oncogenes are converted to oncogenes by mutations int he DNA that cause a gain in function; that is, the protein can now function better in the absence of the normal activating events.

Front 190

190. What are four mechanisms that lead to the conversion of proto-oncogenes to oncogenes?

Back 190

1. Radiation and chemical exposure
2. Transposition/translocation of the entire proto-oncogene
3. Amplification of the proto-oncogene
4. Via oncogenic virus that integrates into the host-cell genome

Front 191

191. Radiation and chemical exposure and conversion of proto-oncogenes to oncogenes

Two ways...

Back 191

Radiation and chemical carcinogens act by:
1. Causing a mutation in the regulatory region of a gene, increasing the rate of production of the proto-oncogene protein
2. Producing a mutation in the coding portion of the oncogene that results in the synthesis of a protein of slightly different AA composition capable of transforming the cell.

Front 192

192. Transposition/translocation of the entire proto-oncogene and conversion of proto-oncogenes to oncogenes

Back 192

The entire proto-oncogene or a portion of it may be transposed or translocated, that is, moved from one position in the genome to another.

In its new location, the proto-oncogene may be expressed under the control of a promoter that is regulated differently than the promoter that normally regulates this gene.

This may allow the gene to be expressed ina tissue where it is not normally expressed or at higher-than-normal levels of expression.

If only a portion of the proto-oncogene is translocated, it may be expressed as a truncated protein with altered properties, or it may fuse with another gene and produce a fusion protein containing portions of what are normally two separate proteins. The truncated or fusion protein may be hyperactive and cause inappropriate cell growth.

Front 193

193. Amplification of the proto-oncogene and conversion of proto-oncogenes to oncogenes

Back 193

The proto-oncogene may be amplified, so that multiple copies of the gene are produced in a single cell. If more genes are active, more proto-oncogene protein will be produced, increasing the growth rate of the cells.

As examples the oncogene N-myc (a cell proliferation transcription factor, related to c-myc) is amplified in some neuroblastomas, and amplification of the erb-B2 oncogene (a growth factor receptor) is associated with several breast CAs.

Front 194

194. Oncogenic virus that integrates into the host-cell genome and conversion of proto-oncogene to oncogene

Back 194

If an oncogenic virus infects a cell, its oncogene may integrate into the host-cell genome, permitting production fo the abnormal oncogene protein.

The cell may be transformed and exhibit an abnormal pattern of growth. Rather than inserting an oncogene, a virus may simply insert a strong promoter into the host-cell genome.

This promoter may cause increased or untimely expression of a normal proto-oncogene.

Front 195

195. Mutations in DNA repair enzymes

Back 195

Repair enzymes are the first line of defense preventing conversion of chemical damage in DNA to a mutation.

DNA repair enzymes are tumor suppressor genes in the sense that errors repaired before replication do not become mutagenic.

If DNA repair enzymes are absent, mutations accumulate much more rapidly, and once a mutation develops in a growth-regulatory gene, a cancer may arise.

Front 196

196. Oncogenes

Back 196

The mutations in oncogenes that give rise to transformation are usually gain-of-function mutations; either a more active protein is produced or an increased amount of the normal protein is synthesized.

Front 197

197. Oncogenes and signal transduction cascades

Back 197

All of the proteins in growth-factor signal transduction cascades are proto-oncogenes.

Front 198

198. Growth factors and growth factor receptors

Back 198

The genes for both growth factors and growth factor receptors are proto-oncogenes.

Growth factors generally regulate growth by serving as ligands that bind to cellular receptors located on the plasma membrane. Binding of ligands to these receptors stimulates a signal transduction pathway in the cell that activates the transcription of certain genes.

If too much of a growth-factor receptor is produced, the target cells may respond by proliferating inappropriately.

Front 199

199. How else can growth factor receptors become oncogenic?

Back 199

Growth factor receptors may also become oncogenic through translocation or point mutations in domains that affect binding of the growth factor, dimerization, kinase activity, or some other aspect of their signal transmission.

In such cases, the receptor transmits a proliferative signal even though the growth factor normally required to activate the receptor is absent. In other words, the receptor is stuck in the "on" position.

Front 200

200. Signal transduction proteins

Back 200

The genes that encode proteins involved in growth factor signal transduction cascades may also be proto-oncogenes.

Consider the monomeric G-protein Ras. Binding of growth factor leads to the activation of Ras. When Ras binds to GTP, it is active, but Ras slowly inactivates itself by hydrolyzing its bound GTP to GDP and Pi. This controls the length of time that Ras is active.

Ras is converted to an oncogenic form by point mutations that decrease the activity of the GTPase domain of Ras, thereby increasing the length of time it remains in the active form.

Front 201

201. Active Ras does what?

Back 201

Ras, when it is active, activates the serine-threonine kinase Raf (a MAP kinase kinase kinase), which activates MEK ( a MAP kinase kinase), which activates MAP kinase.

Front 202

202. Activation of MAP kinase does what...?

Back 202

Activation of MAP kinase results in the phosphorylation of cytoplasmic and nuclear proteins, followed by increased transcription of the transcription factor proto-oncogenes myc and fos.

Note that mutations int he genes for any of the proteins that regulate MAP kinase activity, as well as those proteins induced by MAP kinase activation, can lead to uncontrolled cell proliferation.

Front 203

203. What are transcription factors?

Back 203

Many transcription factors, such as Myc and Fos, are proto-oncoproteins (the products of proto-oncogenes).

Front 204

204. Activation of MAP kinase also does...?

Back 204

MAP kinase, in addition to inducing myc and fos, also directly activates the AP-1 transcription factor through phosphorylation.

AP-1 is a heterodimer formed by the protein products of the fos and jun families of proto-oncogenes.

The targets of AP-1 activation are genes involved in cellular proliferation and progression through the cell cycle, as are the targets of the myc transcription factor.

Front 205

205. Regulation of C-myc

Back 205

The synthesis of the transcription factor C-myc is tightly regulated in normal cells, and it is expressed only during the S phase of the cell cycle.

In a large number of tumor types, this regulated expression is lost, and c-myc becomes inappropriately expressed or overexpressed throughout the cell cycle, driving cells continuously to proliferate.

Front 206

206. What is the net result of alterations in the expression of transcription factors?

Back 206

The net results of alteration in the expression of transcription factors is the increased production of the proteins that carry out the processes required for proliferation.

Front 207

207. Cell cycle regulation

Back 207

The growth of human cells, involving DNA replication and cell division in the cell cycle, is activated by growth factors, hormones, and other messengers. These activators work through cyclins and cyclin dependent kinases (CDK's) that control progression from one phase of the cycle to another.

For quiescent cells to proliferate, they must leave G₀ and enter the G₁ phase of the cell cycle. If the proper sequence of events occurs during G₁, the cells enter the S phase and are committed to DNA replication and cell division. Similarly, during G₂, cells make a commitment to mitotic division.

CDK's are made constantly throughout the cell cycle but require binding of a specific cyclin to be active. Different cyclins made at different times in the cell cycle control each of the transitions.

Front 208

208. How is the activity of the cyclin-CDK complex further regulated?

Back 208

The activity of the cyclin-CDK complex is further regulated through phosphorylation and through inhibitory proteins called cyclin-dependent kinase inhibitors (CKI's).

CKI's slow cell-cycle progression by binding and inhibiting the CDK-cyclin complexes. CDKs are also controlled through activating phosphorylation by CAK (cyclin-activating kinases) and inhibitory hyperphosphorylation kinases.

Front 209

209. What regulatory proteins are involved in determining whether the cell is ready to pass this checkpoint?

Back 209

These regulatory proteins include cdk4 and cdk6, cyclin D, the retinoblastoma gene product (Rb), and a class of transcription factors collectively known as E2F.

Front 210

210. How do these regulatory proteins interact with one another?

Back 210

In quiescent cells, Rb is complexed with E2F, resulting in inhibition of these transcription factors. Upon growth-factor stimulation the cyclin Ds are induced. They bind to cdk4 and cdk6, converting them to active protein kinases.

One of the targets of cyclin/cdk phosphorylation is the Rb protein.

Phosphorylation of Rb releases it from E2F, and E2F is then free to activate the transcription of genes required for entry into S. The Rb protein is a tumor-suppressor gene.

Front 211

211. What are the proteins induced by E2F?

Back 211

The proteins induced by E2F include cyclin E, cyclin A, cdc25A, and proteins required to bind at origins of replication to initiate DNA synthesis.

The synthesis of cyclin E allows it to complex with cdk2, forming another active cyclin complex that retains activity into S phase.

Front 212

212. What is one of the major functions of the cyclin E1-cdk2 complex?

Back 212

One of the major functions of the cyclin E1-cdk2 complex is hyperphosphorylation of the Rb protein, thereby keeping Rb in its inactive state.

Front 213

213. What is the function of Cyclin A?

Back 213

Cyclin A also complexes with Cdk2, and it phosphorylates, and inactivates, the E2F family of transcription factors.

This ensures that the signals are not present for extended periods of time.

Front 214

214. What opposes the progression through the cell cycle?

Back 214

Progression through the cell cycle is opposed by the CKIs. The CKI's regulating cyclin/cdk expression in the G₁ phase of the cell cycle fall into two categories: the Cip/Kip family and the INK4 family.

Front 215

215. What is the function of the Cip/Kip family?

Back 215

The Cip/Kip family members (p21, p27, and p57) have a broad specificity and inhibit all cyclin-CDK complexes.

Front 216

216. What is the function of the INK4 family?

Back 216

The INK4 family, which consists of p15, p16, p18, and p19, are specific for the cyclin D-cdk4/6 family of complexes (INhibitors of cyclin-dependent Kinase-4).

Front 217

217. Regulation of the CKI

Back 217

The regulation of synthesis of different CKI's is complex, but some is induced by DNA damage to the cell and halts cell cycle progression until the damage can be repaired.

For example, the CKI p21 is a key member of this group that responds to specific signals to block cell proliferation. If the damage cannot be repaired, an apoptotic pathway is selected and the cell dies.

Front 218

218. Tumor suppressor genes

Back 218

Like the oncogenes, the tumor-suppressor genes encode molecules involved in the regulation of cell proliferation.

The normal function of tumor suppression proteins is generally to inhibit proliferation in response to certain signals such as DNA damage. The signal is removed when the cell is fully equipped to proliferate; the effect of the elimination of tumor suppressor genes is to remove the brakes on cell growth.

They affect cell-cycle regulation, signal transduction, transcription, and cell adhesion. The products of tumor suppressor genes frequently modulate pathways that are activated by the products of proto-oncogenes.

Front 219

219. How do tumor suppressor genes contribute to the development of cancer?

Back 219

Tumor suppressor genes contribute to the development of cancer when both copies of the gene are inactivated.

This is different from the case of proto-oncogene mutations b/c only one allele of a proto-oncogene needs to be converted to an oncogene to initiate transformation.

Front 220

220. What are the two best understood cell cycle regulators that are also tumor suppressors?

Back 220

1. Retinoblastoma (rb) gene
2. p53 genes

Front 221

221. Retinoblastoma (rb) gene

Back 221

The retinoblastoma gene product, Rb, functions in the transition from G₁ to S phase and regulates the activation of members of the E2F family of transcription factors.

If an individual inherits a mutated copy of the rb allele, there is a 100% chance of that individual developing retinoblastoma, b/c of the high probability that the second allele or rb will gain a mutation.

This is considered familial retinoblastoma. Individuals who do not inherit mutatiosn in rb, but who develop retinoblastoma, are said to have sporadic retinoblastoma, and acquire two specific mutations, one in each rb allele or the retinoblast, during their lifetime.

Front 222

222. p53

Back 222

The p53 protein is a transcription factor that regulates the cell cycle and apoptosis.

Loss of both p53 alleles is found in more than 50% of human tumors. p53 acts as the "guardian of the genome" by halting replication in cells that have suffered DNA damage and targeting unrepaired cells to apoptosis.

Front 223

223. Whne does the level of p53 rise?

Back 223

In response to DNA damaging mutagens, ionizing radiation, or UV light, the level of p53 rises.

Front 224

224. Actions of p53

Back 224

p53, acting as a transcription factor, stimulates transcription of p21.

The p21 gene product inhibits the cyclin/CDK complexes, which prevents the phosphorylation of Rb and release of E2F proteins. The cell is thus prevented from entering S phase.

Front 225

225. What else does p53 do?

Back 225

p53 also stimulates teh transcirption of a number of DNA repair enzymes (including GADD45).

If the DNA is successfully repaired, p53 induces its own downregulation, through the activation of the mdm2 gene.

If the DNA repair was not successful, p53 activates a number of genes invovled in apoptosis, including bax and IGF-BP3.

Front 226

226. WTF is IGF-BP3?!?

Back 226

The IGF-BP3 protein product binds the receptor for insulin-like growth factor, which presumably induces apoptosis by blocking the antiapoptotic signaling by growth factors, and the cell enters a growth fact deprivation mode.

Front 227

227. Regulators of Ras

Back 227

The Ras family of proteins is involved in signal transduction for many hormones and growth factors and is, therefore, oncogenic.

The activity of these pathways is interrupted by GAPs, which vary among cell types.

Front 228

228. What are GAPs?

Give an example of a GAP

Back 228

GTPase-activating proteins

Neurofibromin, the product of the tumor suppressor gene NF-1, is a nervous system specific GAP that regulates the activity of Ras in neuronal tissues.

Front 229

229. How does neurofibromin regulate the activity of Ras in neuronal

Back 229

The growth signal is transmitted so long as the Ras protein binds GTP. Binding of NF-1 to Ras activates the GTPase domain of Ras, which hydrolyzes GTP to GDP, thereby inactivating Ras. Without a functional neurofibromin molecule, Ras is perpetually active.

Front 230

230. Patch and smoothened co-receptor genes

Back 230

These co-receptor genes are an example of tumor suppressors and oncogenes working together.

These co-receptor genes encode the receptor for the hedgehog class of signaling peptides.

These co-receptors normally function to control growth during embryogenesis and illustrate the importance of maintaining a balance between oncogenes and tumor-suppressor genes.

Front 231

231. How do the patch and smoothened co-receptor genes work together?

Back 231

The Patched receptor protein inhibits Smoothened, its co-receptor protein.

Binding of a hedgehog ligand to Patched releases the inhibition of Smoothened, which then transmits an activating signal to the nucleus, stimulating new gene transcription.

Front 232

232. Which is the onco-gene, and which is the tumor suppressor gene - patch or smoothened?

Back 232

Smoothened is a proto-oncogene, and patched is a tumor suppressor gene.

If patched loses its function (definition of a tumor suppressor), then Smoothened can signal the cell to proliferate, even in the absence of a hedgehog signal.

Conversely, if smoothened undergoes a gain-of-function mutation (definition of an oncogene), it can signal in the absence of the hedgehog signal, even in the presence of Patched.

Inherited mutations in either smoothened or patched will lead to an increased incidence of basal cell carcinoma.

Front 233

233. Cadherins

Back 233

The cadherin family of glycoproteins mediates calcium-dependent cell-cell adhesion. Cadherins form intercellular complexes that bind cells together.

They are anchored intracellularly by catenins, which bind to actin filaments.

Front 234

234. E-cadherin

Back 234

Loss of E-cadherin expression may contribute to the ability of cancer cells to detach and migrate in metastasis.

Individuals who inherit a mutation in E-cadherin are sharply predisposed to developing diffuse-type gastric cancer.

Front 235

235. What are the two functions of catenins?

Back 235

In addition to anchoring cadherins to the cytoskeleton, they act as transcription factors.

Front 236

326. β-catenin

Back 236

β-catenin binds to a complex that contains the regulatory protein APC, which activates it for degradation.

When the appropriate signal inactivates APC, β-catenin levels increase, and it travels to the nucleus, where it activates myc and cyclin D1 transcription, leading to cell proliferation.

Front 237

237. What is APC?

Back 237

APC is a tumor-suppressor gene. If it is inactivated, ti cannot bind β-catenin and inhibit cell proliferation.

Mutations in APC or proteins that interact with it are found in the vast majority of sporadic human colon cancer.

Inherited mutations in APC lead to the most common form of hereditary colon cancer, familial adenomatous polyposis.

Front 238

238. What is phosphatidylserine?

Back 238

Phosphatidylserine is a lipid on the inner leaflet of the cell membrane that is exposed on the external surface of apoptotic vesicles.

It is one of the phagocytic markers recognized by macrophages and other nearby phagocytic cells that engulf the apoptotic bodies.

Front 239

239. What can initiate apoptosis?

Back 239

Apoptosis can be initiated by injury, radiation, free radicals or other toxins, withdrawal of growth factors or hormones, binding of pro-apoptotic cytokines, or interactions with cytotoxic T-cells in the immune system.

Front 240

240. What are the 3 phases of apoptosis?

Back 240

1. Initiation phase
2. Signal integration phase
3. Execution phase

Front 241

241. What are caspases?

Back 241

Caspases are cysteine proteases that cleave peptide bonds next to an aspartate residue.

They are present in the cell as procaspases, zymogen-type enzyme precursors that are activated by proteolytic cleavage of the inhibitory portion of their polypeptide chain.

The different caspases are generally divided into two groups according to their function: initiator caspases, which specifically cleave other pro-caspases; and execution caspases, which cleave other cellular proteins involved in maintaining cellular integrity.

Front 242

242. How are the initiator caspases activated?

Back 242

Through two major signaling pathways:
1. The death receptor pathway
2. Mitochondrial integrity pathway

Front 243

243. What do these initiator caspases do?

Back 243

They activate the execution caspases, which cleave protein kinases involved in cell adhesion, lamins that form the inner lining of the nuclear envelope, actin and other proteins required for cell structure, and DNA repair enzymes.

They also cleave an inhibitor protein of the endonuclease CAD. With destruction of the nuclear envelope, additional endonucleases also become activated.

Front 244

244. What is the death receptor pathway to apoptosis?

Back 244

The death receptors are a subset of TNF-1 receptors, which includes Fas/CD95, TNF-Receptor 1 and Death Receptor 3.

These receptors form a trimer that binds TNF-1 or another death ligand on its external domain and adaptor proteins to its intracellular domain.

Front 245

245. What is the activated TNF-receptor complex?

Back 245

The activated TNF-receptor complex forms the scaffold for binding two molecules of procaspase 8, which autocatalytically cleave each other to form active caspase 8.

Caspases 8 and 10 are intiator caspases that activate execution caspases 3, 6, and 7. Caspase 3 also cleaves a Bcl-2 protein, Bid, to a form that activates the mitochondrial integrity pathway to apoptosis.

Front 246

246. What is the mitochondrial integrity pathway to apoptosis?

Back 246

Apoptosis is also induced by intracellular signals indicating that cell death should occur.

Examples of these signals included growth-factor withdrawal, cell injury, the release of certain steroids, and an inability to maintain low levels of intracellular calcium.

All of these treatments, or changes, lead to release of cytochrome c from the mitochondria.

Front 247

247. Cytochrome c

Back 247

Cytochrome c is a necessary protein component of the mitochondrial electron-transport chain that is loosely bound to the outside of the inner mitochondrial membrane. Its release initiates apoptosis.

Front 248

248. What is the Apaf/cytochrome c complex?

What does it do?

Back 248

In the cytosol, cytochrome c binds Apaf. The Apaf/cytochrome c complex binds caspase 9, an intiator caspase, to form an active complex called the apoptosome.

The apoptosome, in turn, activates execution caspases 3, 6, and 7 by zymogen cleavage.

Front 249

249. What family of proteins integrates pro-death and anti-death signals?

Back 249

The Bcl-2 family members are decision makers that integrate pro-death and anti-death signals to determine whether the cell should commit suicide. Both pro-apoptotic and anti-apoptotic members of the Bcl-2 family exist.

Front 250

250. What are the two ways that Bcl-2 proteins have of antagonizing death signals?

Back 250

1. They insert into the outer mitochondrial membrane to antagonize channel forming pro-apoptotic factors, thereby decreasing cytochrome c release.

2. They may also bind cytoplasmic Apaf so that it cannot form the apoptosome complex.

Front 251

251. What are the two categories of pro-apoptotic family members?

Back 251

1. Ion-channel-forming members

2. BH3-only members

Front 252

252. What are the ion-channel-forming members?

Back 252

The pro-death ion channel forming members, such as Bax, are very similar to the anti-apoptotic family members, except that they do not contain the binding domain for Apaf.

They have the other structural domains, however, and when they dimerize with pro-apoptotic BH3-only members in the outer mitochondrial membrane, they form an ion channel that promotes cytochrome c release rather than inhibiting it.

Front 253

253. What are the BH3-only members?

Back 253

The pro-death BH3-only proteins (e.g. Bim and Bid) contain only the structural domain that allows them to bind to other Bcl-2 family members (the BH3 domain), and not the domains for binding to the membrane or forming ion channels.

Their binding activates the pro-death family members and inactivates the anti-apoptotic members.

Front 254

254. What happens when a cell receives a signal from a pro-death agonist?

Back 254

When a cell receives a signal from a pro-death agonist, a BH3 protein like Bid is activated.

The BH3 protein activates Bax, which stimulates release of cytochrome c.

Front 255

255. How is the apoptosome formed?

Back 255

Normally, Bcl-2 acts as a death antagonist by binding Apaf and keeping it in an inactive state.

However, at the same time that Bid is activating Bax, Bid also binds to Bcl-2, thereby disrupting the Bcl-2/Apaf complex and freeing Apaf to bind to released cytochrome c to form the apoptosome.

Front 256

256. What is one way that cancer cells bypass apoptosis?

Back 256

One of the ways this occurs is through activation of growth-factor-dependent signaling pathways that inhibit apoptosis, such as the PDGF/Akt/BAD pathway.

Nonphosphorylated BAD acts like Bid in promoting apoptosis. Binding of the platelet derived growth factor to its receptor activates PI-3 kinase, which phosphorylates and activates the serine-threonine kinase Akt).

Front 257

257. Activation of Akt results in ...?

Back 257

Activation of Akt results in the phosphorylation of the pro-apoptotic BH3-only protein BAD, which inactivates it.

Front 258

258. What is one of the features of neoplastic transformation?

Back 258

The loss of growth-factor dependence for survival.

Front 259

259. MAP kinase

Back 259

The MPA kinase pathway is also invovled in regulating apoptosis and sends cell-survival signals.

MAP kinase kinase phosphorylates and activates another protein kinase known as RSK.

Like Akt, RSK phosphorylates BAD and inhibits its activity.

Thus, BAD acts as a site of convergence for the PI-3 kinase/Akt and MAP kinase pathways in signaling cell survival.

Front 260

260. What genes mutations can be responsible for basal cell carcinoma?

Back 260

Patched and Smoothened are the receptor and co-receptor for the signaling peptide, sonic hedgehog.

Either mutation of smoothened, or inactivation of patched, can give rise to basal cell carcinoma.

Front 261

261. What viruses are associated with cancer?

Back 261

Three RNA retroviruses are associated with the development of cancer in humans:

1. HTLV-1
2. HIV
3. HepC

Front 262

262. HTLV-1

Back 262

HTLV-1 causes adult T-cell leukemia.

The HTLV-1 genome encodes a protein Tax, which is a transcriptional coactivator. The cellular proto-oncogenes c-sis and c-fos are activated by Tax, thereby altering the normal controls on cellular proliferation and leading to malignancy.

Thus, tax is a viral oncogene without a counterpart in the host-cell genome.

Front 263

263. HIV

Back 263

The HIV genome encodes a protein, Tat, a transcription factor that activates transcription of the IL-6 and IL-10 genes in infected T-cells.

IL-6 and IL-10 are growth factors that promote proliferation of T-cells, and thus their increased production may contribute to the development of non-Hodgkin's lymphoma.

Tat can also be released from infected cells and act as an angiogenic growth factor. This property is thought to contribute to the development of Kaposi sarcoma.

Front 264

264. DNA viruses

Back 264

3 DNA families, SV40, papilomavirus, and adenovirus, encode proteins that inactivate pRb and p53.

By interfering with the cell cycle checkpoints, the oncoproteins increase the chance that mutations in oncogenes and tumor-suppressor genes will be incorporated into the genome of infected cells.

The Epstein-Barr virus encodes a Bcl-2 protein that restricts apoptosis of the infected cell.

Front 265

265. Bleeding problems in leukemia

Back 265

Patients with leukemia experience a variety of hemorrhagic manifestations caused by a decreased number of platelets.

B/c of the uncontrolled proliferation of WBCs within the limited space of the marrow, the normal platelet precursors (the megakaryocytes) int he marrow are squeezed or crowded and fail to develop into mature platelets.

Consequently, the number of mature platelets in the circulation falls, and a thrombocytopenia develops.

Front 266

266. Moles

Back 266

Moles (nevi) are tumors of the skin.

They are formed by melanocytes that have been transformed from highly dendritic single cells interspersed among other skin cells to round oval cells that grow in aggregates or nests.

Front 267

267. What is Burkitt lymphoma?

Back 267

Burkitt lymphoma is a general name for a number of types of B-cell malignancies, resutls from a traslocation between chromosome 8 & 14.

The translocation of genetic material moves the proto-oncogene transcription factor c-myc to chromosome 14.

The translocated gene is now under the control of the promoter regions for the Ig heavy-chain gene, which leads to inappropriate overexpression of c-myc.

The result may be uncontrolled cell proliferation and tumor development. All subtypes of Burkitt lymphoma contain this translocation. Epstein-Barr virus infection of B-cells is also associated with certain types of Burkitt lymphoma.

Front 268

268. CML & the Philadelphia chromosome

Back 268

The Philadelphia chromosome results from a reciprocal translocation between the long arms of chromosome 9 & 22.

As a consequene, a fusion protein is produced that contains the N-terminal region of the Bcr protein from chromosome 22 and the C-terminal region of the Abl protein from chromosome 9.

Abl is a proto-oncogene, and the resulting fusion protein (Bcr-Abl) has lost its regulatory region and is constitutively active. When ti is active, ABL stimulates the Ras pathway of signal transduction, leading to cell proliferation.

Front 269

269. BRCA1 and BRCA2 genes and cancers

Back 269

BRCA1 mutations are also linked to ovarian cancer and BRCA2 mutations are not.

BRCA2 mutations have been linked to pancreatic cancer, whereas BRCA1 mutations have not.

Men with inherited BRCA2 mutations develop breast CA, but men who carry BRCA1 mutations do not.

Front 270

270. HER2

Back 270

The gene for the human epidermal growth-factor receptor (HER2) is overexpressed in 10-20% of breast CAs.

When this gene is overexpressed, the prognosis for recovery is poor, as the patients display shorter disease free intervals, increased risks for metastasis, and a resistance to therapy.

Front 271

271. Herceptin

Back 271

A drug has been developed that recognizes and blocks the receptor's action (herceptin, a monoclonal antibody with specificity to the HER2 protein).

However, not all tumor that overexpress HER2 are responsive to herceptin.

Front 272

272. What genes play a role in development of malignant melanoma?

Back 272

10% of melanomas tend to run in families. Some of the suspected melanoma-associated genes include the tumor-suppressor gene p16 (an inhibitor of cdk 4) and CDK4.

Front 273

273. Mutated Bcl-2

Back 273

When Bcl-2 is mutated, and oncogenic, it is usually overexpressed for example, in follicular lymphoma and CML.

Overexpression of Bcl-2 disrupts the normal regulation of pro and anti apoptotic factors and tips the balance to an antiapoptotic stand.

This leads to an inability to destroy cells with damaged DNA, such that mutations can accumulate within the cell.

Bcl-2 is also a multidrug resistant protein and if it is overexpressed it will block the induction of apoptosis by antitumor agents by rapidly removing them from the cell.

Front 274

274. What is Gleevec?

Back 274

A new treatment for CML - the fusion protein Bcr-Abl is found only in transformed cells that express the Philadelphia chromosome and not in normal cells.

Gleevec was designed to specifically bind to and inhibit only the active site of the fusion protein and not the normal protein. Gleevec was successful in blocking Bcr-Abl function, thereby stopping cell proliferation and in some cells inducing apoptosis, so the cells would die. B/c normal cells do not express the hybrid protein, they were not affected by the drug.

Front 275

275. What were some problems with Gleevec?

Back 275

The problem with this treatment is that some patients suffered relapses, and when their Bcr-Abl proteins were studied it was found that in some patients the fusion protein has a single AA substitution near the active site that prevented Gleevec from binding to the protein.

Other patients has an amplification of the Bcr-Abl gene product.

Front 276

276. What mutations are associated with malignant melanomas?

Back 276

1. ras - gain of function in growth signal transduction oncogene
2. p53 (loss)
3. p16 (loss)
4. Cdk4 (gain)
5. Cadherin/β-catenin regulation (loss)

Front 277

277. What are the two classes of tumors?

Back 277

1. Benign
2. Malignant

The type of neoplasm is based on the characteristics of its parenchyma.

Front 278

278. What are the two basic components of a tumor?

Back 278

1. Proliferating neoplastic cells that constitute their parenchyma

2. Supportive stroma made up of connective tissue and blood vessels.

Front 279

279. What is the suffix for naming benign tumors?

What is the nomenclature of benign epithelial tumors based on?

Back 279

-oma

Based on the histogenesis and architecture

Front 280

280. Adenoma

Back 280

term applied to a benign epithelial neoplasm that forms glandular patterns as well as to tumors derived from glands but not necessarily reproducing glandular patterns.

Front 281

281. Cystadenomas

Back 281

Adenomas producing large cystic masses seen typically in the ovary.

Front 282

282. Papillomas

Back 282

Epithelial tumors forming microscopic or macroscopic finger like or warty projections from epithelial surfaces.

Front 283

283. Polyp

Back 283

A tumor projecting from the mucosa into the lumen of a hollow viscus, for example stomach or colon.

Front 284

284. What are the two general categories of malignant tumors?

Back 284

1. Carcinomas
-arise from epithelial cells

2. Sarcomas
-arise from mesenchymal tissue

Front 285

285. Mixed tumors

Back 285

Infrequently, divergent differentiation of a single line of parenchymal cells into another tissue creates what is called mixed tumors. These tumor contain epithelial components scattered within a mycoid stroma that sometimes contains islands of apparent cartilage or even bone.

Example: mixed tumor of salivary gland origin and pleomorphic adenoma

They are derived from one germ cell layer that differentiates into more than one parenchymal cell type.

Front 286

286. Feature of most neoplasms, even mixed

Back 286

The great majority of neoplasms, even mixed tumors, are composed of cells representative of a single germ layer.

Front 287

287. Teratomas

Back 287

Teratomas are made up of a variety of parenchymal cell types, representative of more than one germ cell layer, usually all three.

They arise from totipotent cells that retain the ability to form endodermal, ectodermal, and mesenchymal tissues.

Such tumors are found principally in the testes and ovary.

Front 288

288. What are the two non-neoplastic lesions that grossly resemble tumors?

Back 288

1. Choristoma
-Ectopic rests of non-transformed tissue: ex: pancreatic cells under the small bowel mucosa.

2. Hamartoma
-Masses of disorganized tissue indigenous to a particular site: example: nodules in the lungs may contains islands of cartilage, bronchii, and blood vessels.

Front 289

289. Seminomas

Back 289

Seminoma is a form of testicular carcinoma that tends to spread to lymph nodes along the iliac arteries and aorta.

Further, these tumors are extremely radiosensitive and can be eradicated by radiotherapy

Front 290

290. Embryonal carcinoma of the testis

Back 290

Embryonal carcinoma of the testis is not radiosensitive and tends to invade locally beyond the confines of the testis and spread throughout the body.

Front 291

291. What are the four phases of malignant tumors?

Back 291

1. Malignant change in the target cell, referred to as transformation
2. Growth of the transformed cell
3. Local invasion
4. Distant metastases

Front 292

292. What is differentiation?

Back 292

Differentiation refers to the extent to which tumor cells resemble comparable normal cells, both morphologically, and functionally. Cells within most benign tumors closely mimic corresponding normal cells.

Lack of differentiation is called anaplasia.

Front 293

293. Malignant neoplasms

Back 293

Malignant neoplasms, composed of undifferentiated cells are said to be anaplastic. Lack of differentiation, o anaplasia, is considered a hallmark of malignant transformation.

Front 294

294. Well-differentiated cancer vs. undifferentiated malignant tumor

Back 294

The well differentiated cancer evolves from maturation or specialization of undifferentiated cells as they proliferate, whereas the undifferentiated malignant tumor derives from proliferation without complete maturation of the transformed cells.

Front 295

295. What are the features used to characterize anaplasia?

Back 295

1. Nuclear and cellular pleomorphism
2. Abnormal nuclear morphology
3. Abundant mitoses
4. Loss of polarity
5. Other changes (ex: formation of tumor giant cells)

Front 296

296. Pleomorphism

Back 296

Variation in the shape and size of nuclei

Front 297

297. Abnormal nuclear morphology

Back 297

Darkly stained nuclei (hyperchromatic) frequently containing a prominent nucleoli.

The nuclei are disproportionately large for the cells, and the nucleus to cytoplasm ratio may approach 1:1.

Front 298

298. Abundant mitoses

Back 298

Reflecting proliferative activity. Mitotic figures may be abnormal.

The presence of mitoses, however, does not necessarily indicate that a tumor is malignant or that the tissue is neoplastic.

Front 299

299. Loss of polarity

Back 299

Anaplastic cells show disturbed orientation and tend to form anarchic, disorganized masses.

Front 300

300. Other changes

Back 300

Another feature of anaplasia is the formation of tumor giant cells, some possessing only a single large polyploid nucleus or multiple nuclei.

Front 301

301. Poorly differentiated, anaplastic tumors

Back 301

Poorly differentiated, anaplastic tumors also demonstrate total disarray of tissue architecture. Thus, in an anaplastic uterine cervical malignancy, the normal orientation of squamous epithelial cells relative to each other is lost.

Front 302

302. Well differentiated tumors

Back 302

Well differentiated tumors, benign or malignant, tend to retain the functional characteristics of their normal parts. Thus, there may be hormone production by endocrine tumors or keratin production by squamous epithelial tumors

Front 303

303. What does dysplasia mean?

Back 303

Dysplasia refers to disorderly but non-neoplastic growth; it is usually encountered in epitheilia.

Pleomorphism, hyperchromasia, and loss of normal orientation may occur, without sufficient changes to merit the designation of malignancy.

Mild degrees of dysplasia do not always result in cancer and are often reversible when the inciting cause is removed.

Front 304

304. Carcinoma in situ

Back 304

When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is considered a preinvasive neoplasm and is referred to as carcinoma in situ.

Front 305

305. Invasive

Back 305

Once the tumor cells move beyond the normal confines, the tumor is said to be invasive.

Front 306

306. Relation between tumor differentiation and anaplasia

Back 306

Despite exception, the more rapidly growing and the more anaplastic a tumor, the less likely it is that there will be specialized functional activity.

The cells in benign tumors are almost always well differentiated and resemble their normal cells of origin; the cells in cancer are more or less differentiated but some loss of differentiation is always present.

Front 307

307. Rates of growth

Back 307

Most malignant tumors grow ore rapidly than benign tumors.

Nevertheless, some cancers grow slowly for years, and only then enter a phase of rapid growth; other expand rapidly from the onset.

Growth of cancers arising from hormone-sensitive tissues (breast) may be affected by hormonal variations associated with pregnancy and menopause.

Ultimately, the progression of tumors and their growth rates are determined by an excess of cell production over cell loss.

Front 308

308. What are the three main factors that determine the rate of growth of a tumor?

Back 308

1. Doubling time of tumor cells
2. Fraction of tumor cells that are in the repilicative pool
3. Rate at which cells are shed and lost in the growing lesion

Front 309

309. Cell-cycle time of tumor cells

Back 309

Fast growing tumors can have a high cell turnover, that is rates of proliferation and apoptosis are both high.

Front 310

310. Growth fraction

Back 310

The proportion of cells in a tumor population that are actively proliferating is called the growth fraction.

The growth fraction of tumor cells has a profound impact on susceptibility to therapeutic intervention, b/c most anti-cancer treatments act only on cells that are in cycle.

Front 311

311. Growth rate and differentiation

Back 311

Malignant tumors grow more rapidly than do benign lesions.

In general (but not always), the growth rate of tumors correlates with the level of differentiation.

Front 312

312. Growth fraction and chemotherapy

Back 312

The growth faction of tumor cells has a profound effect on their susceptibility to cancer chemotherapy. B/c most anticancer agents act on cells that are in cycle, it is not difficult to imagine that a tumor that contains 5% of all cells in the replicative pool will be slow growing but relatively refractory to treatment with drugs that kill dividing cells.

Front 313

313. How long is the latent period before which a tumor becomes clinically detectable?

Back 313

The latent period before which a tumor becomes clinically detectable is unpredictable but typically much longer than 90 days, up to many years for most solid tumors.

Front 314

314. Cancer stem cells and cancer cell lineages

Back 314

A clinically detectable tumor (typically containing 10⁹ cells) is a heterogeneous population of cells originating from the clonal growth of the progeny of a single cell.

Tumor stem cells have the capacity to initiate and ultimately sustain tumor growth; however, these cells constitute a small fraction of the total population (0.1-2%) and have an extremely low rate of replication.

Front 315

315. Local invasion in benign tumors

Back 315

Most benign tumors grow as cohesive expansile masses that develop a rim of condensed connective tissue, or capsule, at the periphery.

These tumors do not penetrate the capsule or the surrounding normal tissues, and the plane of cleavage between the capsule and the surrounding tissues facilitates surgical enucleation.

Front 316

316. Local invasion in malignant tumors

Back 316

Malignant neoplasms are invasive and infiltrative, and destroy normal tissues surrounding them. They lack a well defined capsule and plane of cleavage, making enucleation difficult or impossible.

Consequently, surgical treatment of such tumors requires removal of a considerable margin of healthy and apparently uninvolved tissue.

Front 317

317. Aside from metastases, what is the most reliable feature that differentiates malignant from benign tumors?

Back 317

Invasiveness

Front 318

318. In situ epithelial cancers

Back 318

In situ epithelial cancers display the cytologic features of malignancy without invasion of the basement membrane.

They may be considered one step removed from invasive cancer; with time, most penetrate the basement membrane and invade the subepithelial stroma.

Front 319

319. Metastasis

Back 319

This is the single most important feature distinguishing benign from malignant tumors.

The process of metastasis involves invasion of lymphatics, blood vessels, or body cavities by tumor, followed by transport and growth of secondary tumor cell masses that are discontinuous with the primary tumor.

Front 320

320. What are the three routes by which metastasis occurs?

Back 320

1. Spread into the body cavities
2. Invasion of lymphatics
3. Hematogenous spread

Front 321

321. Spread into the body cavities

Back 321

This occurs by seeding surfaces of the peritoneal, pleural, pericardial, or subarachnoid spaces.

Carcinoma of the ovary, for example, spreads transperitoneally to the surface of the liver or other abdominal viscera.

Front 322

322. Invasion of lymphatics

Back 322

This is followed by transport of tumor cells to regional nodes and, ultimately, other parts of the body; it is common in the initial spread of carcinomas.

Although tumors do not contain functional lymphatics, lymphatic vessels at tumor margins are apparently sufficient to facilitate lymphatic spread.

Lymph nodes in the lymphatic drainage of tumors are freq enlarged; in some cases, this results from the growth of metastatic tumor cells, but in other cases can result from nodal reactive hyperplasia to tumor antigens.

Front 323

323. Hematogenous spread

Back 323

This is typical of all sarcomas but also is the favored route for certain carcinomas (e.g. those originating in the kidney).

B/c of their thinner walls, veins are more freq invaded than arteries, and metastasis follows the pattern of venous flow; understandably, lung and liver are the most common sites of hematogenous metastases.

Other major sites of hematogenous spread include brain and bones.

Front 324

324. When does tumor growth autonomy occur?

Back 324

Tumor growth autonomy occurs when the normal steps of cell proliferation occur in the absence of growth-promoting signals.

Front 325

325. Normal cell proliferation involves what five steps that can potentially be subverted by oncogenes?

Back 325

1. Growth factor binding to cell surface receptor
2. Transient and limited activation of the growth factor receptor with activation of signal transduction proteins on the cytoplasmic side of the plasma membrane
3. Transmission - via second messengers or signal transduction molecules - of signal to the nucleus.
4. Induction and activation of nuclear regulatory factors that initiate DNA transcription
5. Entry and progression of the cell through the cell cycle

Front 326

326. Again, what are oncogenes?

What are proto-oncogenes?

Back 326

Oncogenes are genes that promote autonomous cell growth in cancer cells

Proto-oncogenes are normal cellular genes that affect growth and differentiation

Front 327

327. What are onco-proteins?

Back 327

Onco-proteins are the protein products of oncogenes; they resemble the normal products of protooncogenes except that they are devoid of normal regulatory elements.

Front 328

328. What are the three ways by which proto-oncogenes can be converted into oncogenes?

Back 328

1. Point mutations
2. Chromosomal rearrangements
3. Gene amplification

Front 329

329. Are most human tumors caused by v-oncs (viral oncogenes) or by c-oncs (cellular oncogenes)?

Back 329

Most human tumors are not caused by v-oncs, but rather by c-oncs.

The mode of proto-oncogene activation is called insertional mutagenesis.

Front 330

330. What is included in the DNA of spontaneously arising cancers?

What was the first sequence found?

Back 330

DNA of spontaneously arising cancers contains oncogenic sequences, or oncogenes.

One of the first oncogenic sequences detected in cancers was a mutated form of the RAS proto-oncogene.

Front 331

331. How are oncoproteins that are encoded by oncogenes different than their normal counterparts?

Back 331

Oncoproteins encoded by oncogenes generally serve similar functions as their normal counterparts.

However, b/c they are constitutively expressed, oncoproteins endow the cell with self-sufficiency in growth.

Front 332

332. Growth factors

Give an example of one.

Back 332

Many cancer cells develop growth self sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. They are also then sensitive/responsive to autocrine stimulation.

The protooncogene SIS, which encodes the beta chain of platelet derived growth factor (PDFG) is over produced in many tumors, especially low grade astrocytomas and osteosarcomas.

Front 333

333. Are growth factor genes altered or mutated in tumors?

Back 333

No, in most instances, the growth factor gene itself is not altered or mutated.

Tumors form from over expression or secretion of growth factors.

Front 334

334. Is increased growth factor production sufficient by itself for neoplastic transformation?

Back 334

No, increased growth factor production by itself is not sufficient for neoplastic transformation.

Extensive cell proliferation, in all likelihood, contributes to the malignant phenotype by increasing the risk of spontaneous or induced mutations in the cell population.

Front 335

335. What are growth factor receptors and what do they have to do with mutations?

Back 335

Seceral oncogenes encode growth factor receptors. Both structural alterations (mutations) and overexpression fo the receptor genes have been found in association with malignant transfromation.

Mutations in several tyrosine kinase types of growth factor receptors lead to their constitutive activation without binding to their ligands.

Front 336

336. What is an example of a gene involved with growth factor receptors and tumor formation?

Back 336

Mutations and rearrangements of the RET gene occur in MEN2A, MEN2B, and papillary carcinoma of the thyroid.

Front 337

337. How are the mutated growth factor receptors different than normal ones?

Back 337

The oncogenic versions of these are associated with constitutive dimerization and activation without binding to the growth factor.

Hence, the mutant receptors deliver continuous mitogenic signals to the cell.

Front 338

338. What specific type of mutations cause MEN2A? Where? How?

Back 338

Point mutations in the extracellular domain of the RET protooncogene cause constitutive dimerization and activation, leading to medullary thyroid carcinomas and also adrenal and PTH tumors.

Front 339

339. What specific type of mutations cause MEN2B? Where? How?

Back 339

In MEN2B, point mutations in the RET cytoplasmic catalytic domain alter the substrate specificity of the tyrosine kinase and lead to thyroid and adrenal tumors but no involvement of the PTH gland.

Front 340

340. Complete loss of RET function results in...?

Back 340

Complete loss of RET function results in Hirschsprung disease, in which their is a lack of development of intestinal nerve plexuses.

Front 341

341. c-MET is overexpressed in which type of carcinoma?

Back 341

In sporadic papillary thyroid carcinomas, c-MET is overexpressed in almost every case.

In these tumors, increased expression of c-MET is not caused by gene mutation but results from enhanced transcription fo the gene.

Front 342

342. Overexpression commonly involves members what what receptor family?

Back 342

Overexpression commonly involves members of the epidermal growth factor receptor family

Front 343

343. ERB B1 overexpression

Back 343

ERB B1 is overexpressed in the majority (80%) of squamous cell carcinomas of the lung, in 50% or more of high-grade astrocytomas called gliobastomas, in 80-100% of head and neck tumors.

Front 344

344. ERB B2 overexpression

Back 344

ERB B2 (AKA HER 2/Neu) is amplified in approx 25% of breast cancers and in adenocarcinomas of the, ovary, lung, stomach, and salivary glands.

In breast cancers with amplified ERB B2, the prognosis is poor, presumably b/c their cells are sensitive to smaller quantities of growth factors.

Front 345

345. What are signal transducing proteins?

What is the best and most well studied example of a signal transducing oncoprotein?

Back 345

These proteins are biochemically heterogeneous; the best studied is the RAS family of GTP binding proteins (G protein)

Front 346

346. What is the single most common abnormality of dominant oncogenes in human tumors?

Back 346

Point mutation of RAS familiy genes is the signle most common abnormality of dominant oncogenes in human tumors.

Approx 1-20% of all human tumors contain mutated versions of RAS proteins.

Front 347

347. Normal RAS proteins

Back 347

Normal RAS proteins flip back and forth between an activated GTP bound signal transmitting form and an inactive GDP bound form.

The conversion of active RAS to inactive RAS is mediated by its intrinsic GTPase activity, and is augmented by a family of GTPase-activating proteins (GAPs).

Front 348

348. Mutant RAS proteins

Back 348

Mutant RAS proteins bind GAPs, but still lack GTPase activity, and hence remain trapped int he signal transmitting GTP bound form.

In this state, the active RAS turns of the MAP kinse pathway and promotes mitogenesis.

Front 349

349. Alterations in nonreceptor tyrosine kinases

What is an example?

Back 349

An example in this category is the c-ABL gene, which in its normal form exerts a regulated tyrosine kinase activity.

In chronic myeloid leukemia, translocation fo the c-ABL with fusion to the BCR gene produce a hybrid protein with potent, unregulated tyrosine kinase activity.

Front 350

350. Transcription factors

How are their oncogenic versions different?

Back 350

The products of MYC, MYB, JUN, and FOB oncogenes are nuclear proteins.

They are expressed in a highly regulated fashion during proliferation of normal cells, and regulate transcription of growth-related genes.

Their oncogenic versions are typically associated with overexpression.

Front 351

351. What does dysregulation of MYC result in?

Back 351

Dysregulation of MYC expression (E.g. due to gene duplication, rearrangements with gene translocation, or changes in posttranslational regulation) occurs in Burkitt lymphoma, neuroblastomas, and small cell cancer of the lung.

Front 352

352. Cyclins and CDKs

Back 352

Overexpression of cyclin D (and CDK4 is common in many types of cancer, with loss of the checkpoint in the G₁/S transition.

Front 353

353. Overexpression of cyclin D causes...?

Amplification of CDK4 gene results in...?

Expression of cyclin E is associated with...?

Back 353

Cyclin D overexpression occurs in cancers of the breast, head, neck, esophagus, liver, and in a subset of lymphomas (mantle cell lymphomas).

Amplifications of the CDK4 gene occurs in sarcomas and glioblastomas.

Cyclin E is overexpressed in breast cancers, and the level of expression correlates with disease progression and survival.

Front 354

354. Insensitivity to growth inhibitory signals; tumor suppressor genes

Back 354

Cancers may arise not only by activation of growth promoting oncogenes, but also by inactivation of genes that normally suppress cell proliferation (tumor suppressor genes)

Front 355

355. What is the prototypic tumor suppressor gene?

What is its relevance?

Back 355

The RB gene located on chromosome 13q14 is the prototypic tumor suppressor gene.

It is relevant to the pathogenesis of the childhood tumor retinoblastoma; 40% are familial and the rest are sporadic.

Front 356

356. What is LOH?

Back 356

Cancer develops when the cell becomes homozygous for the mutant allele, or put another way, when the cell loses heterozygosity (LOH) for the normal RB gene.

B/c the RB gene is associated with cancer when both normal copies are lost, it is sometimes referred to as a recessive cancer gene.

Front 357

357. How does the RB gene stand as a paradigm for several other genes?

Back 357

These other genes act similarly.

For example, one or more of genes on the short arm of chromosome 11 play a role in the formation of Wilms tumor, hepatoblastoma, and rhabdomyosarcoma.

The von Hippel Lindau gene is a tumor suppressor gene that causes familial clear cell renal carcinomas and is also involved in sporadic forms of the same tumor.

Consistent and non-random LOH has provided important clues to the location of several tumor suppressor genes.

Front 358

358. What does the RB gene do?

Back 358

The RB gene product regulates the advancement of cells from the G₁ to S phase of the cell cycle.

With RB mutations, E2F transcription factor regulation is lost, and cells continue to cycle in the absence of a growth stimulus.

Several oncogenic DNA viruses (e.g. HPV) synthesize proteins that bind to pRb and displace the E2F transcription factors, thereby contributing to persistent cell cycling.

Transforming growth factor beta is a growth-inhibiting cytokine that upregulates CDK inhibitors, thus preventing RB hyperphosphorylation.

Front 359

359. At least one of what four key regulators of the cell cycle is dysregulated in malignant transformation?

Back 359

1. p16INK4a
2. Cyclin D
3. CDK4
4. RB

Front 360

360. What is the function of the p53 gene?

Back 360

The function of the normal p53 gene is to prevent the propagation fo genetically damaged cells. It does this by arresting the cell cycle in G₁ which is mediated by p53-dependent transcription of the CDK inhibitor p21.

If the damage can't be repaired, p53 induces apoptosis by causing increased transcription of the pro-apoptic gene BAX.

Front 361

361. p53 mutations and Li-Fraumeni syndrome

Back 361

A little over 50% of human tumors contain mutations in this gene. Homozygous loss of the p53 gene activity can occur in virtually every type of cancer.

Those who inherit a mutant copy copy of the p53 gene (i.e. Li-Fraumeni syndrome) are at a high risk of developing a malignant tumor by inactivation of the second nromal allele in somatic cells.

Front 362

362. p53 function and response to chemotherapy

Back 362

Tumors that retain normal p53 are more likely to respond to such therapy than tumors that carry mutant alleles of the gene.

By contrast, tumors such as lung cancers and colorectal cancer, which freq carry p53 mutations, are relatively resistant to chemotherapy and radiotherapy.

Front 363

363. APC/β-catenin pathway

Back 363

Those born with one mutant allele of this gene develop thousands of adenomatous polyps in the colon, of which one or more develop into colonic cancers.

APC mutations with homozygous loss are also found in 70-80% of sporadic colon cancers

β-catenin mutations are associated with more than 50% of hepatoblastomas and approx 20% of HCCs.

Front 364

364. What is the function of the normal APC protein?

Back 364

The normal APC protein binds to and regulates the degradation of β-catenin in the cytoplasm; in the absence of the APC protein, β-catenin levels increase, and it translocates to the nucleus where it up-regulates cellular proliferation by increasing the transcription of c-MYC, cyclin D1, and other genes.

Thus, APC is a negative regulator of β-catenin.

Front 365

365. APC and WNT signaling

Back 365

APC is a component of the WNT signaling pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development.

WNT signaling is also required for self-renewal of hematopoietic stem cells.

An important function of APC protein is to down regulate β-catenin; thus, in the absence of WNT-signaling, APC causes degradation of β-catenin, prevening its accumulation in the cytoplasm. It does so by forming a macromolecular complex with β-catenin, which results in the degradation of β-catenin.

Front 366

366. What happens with the loss of APC?

Back 366

With the loss of APC, the cell behaves as if it is under continuous WNT signaling and there is an excess of free β-catenin.

Front 367

367. INK4a/ARF locus

Back 367

Mutations of this locus have been found in about 20% of familial melanoma. Among sporadic tumors, p16INK4a mutations are present in up to 50% of pancreatic adenocarcinomas and squamous cell carcinomas of the esophagus.

Mutated alleles of p16INK4a present in these tumors have lost their capacity to block cyclin D-CDK4 activity and to prevent RB phosphorylation during the cell cycle.

Front 368

368. The TGF-β pathway

Back 368

This pathway up-regualates growth inhibitory genes, including CDK inhibitor, by binding to TGF-β receptors.

The gene encoding the type II TGF-β receptor is inactivated in more than 70% of colon cancers that develop in HNPCC patients, in sporadic colon cancer with microsatellite instability, and ingastric cancers in HNPCC patients.

Front 369

369. What are the effects of mutated TGF-β receptors?

Back 369

The mutated TGF-β receptors prevent the growth restraining effects of TGF-β.

In addition downstream mediated of the TGF-β signaling cascade (e.g. SMAD 2 - colorectal and SMAD 4 - pancreatic) are also mutated or inactivated in pancreatic and colorectal tumors.

Front 370

370. NF-1 gene and neurofibromatosis

Back 370

This tumor suppressor gene regulates signal transduction by the RAS pathway. Homozygous loss of NF-1 impairs the conversion of active GTP bound RAS to inactive GDP bound RAS; cells are continuously stimulated to divide.

As with APC, germ line inheritance of one mutant allele of NF-1 predisposes to the development of numerous benign neurofibromas when the second NF-1 gene is lost or mutated.

Front 371

371. NF-2 gene

Back 371

Germ line mutatiosn in the NF2 gene predispose to development of neurofibromatosis type 2.

The product of the NF-2 gene, called merlin, shows a great deal of homology with the red cell membrane cytoskeletal protein 4.1.

Merlin binds to actin and to CD44 - cells lacking merlin are not capable of establishing stable cell-to-cell junctions are are insensitive to normal growth arrest signals generated by cell-to cell contact.

Front 372

372. VHL

Back 372

Germ line mutations of the von Hippel Lindau gene on chromosome 3p are associated with:
1. Hereditary renal cell cancers
2. Pheochromocytomas
3. Hemangioblastomas of the CNS
4. Retinal angiomas
5. Renal cysts

The VHL protein forms a complex that functions as ubiquitin ligases. Lack of VHL activity prevents ubiquination and degradation of HIF-1 and is associated with increase levels of angiogenic growth factors.

Front 373

373. PTEN

Back 373

Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN) gene, mapped on chromosome 10q23, is freq deleted in many cancers but at particularly high freq in endometrial carcinomas and glioblastomas.

PTEN activity causes cell cycle arrest and apoptosis as well as inhibition of cell motility via increasing the transcription of the Cip/Kip cell cycle inhibitor. With loss of PTEN, cells are released into the cell cycle.

Front 374

374. Wt-1 gene

Back 374

Mutational inactivation of WT-1, either in the germ line or in the somatic cells, is associated with the development of Wilms tumors.

The WT-1 protein is a transcriptional activator of genes involved in renal and gonadal differentiation; although not precisely known, the tumorigenic function of WT-1 deficiency is connected to its role in the differentiation of genitourinary tissues.

Front 375

375. Cadherins

Back 375

Loss of cadherins can favor the maligant phenotype by allowing easy disaggregation of cells, which can then invade locally or metastasize.

Reduced cell surface expression of E-cadherin has been noted in many types o cancers.

Germ line mutatiosn of the E-cadherin gene can predispose to familial gastric carcinoma, and mutation of the gene and decreased E-cadherin expression are present in a variable proportion of gastric cancers.

Front 376

376. KLF6

Back 376

KLF6 encodes a transcription factor that has many target genes.

KLF6 is mutated in more than 70% of primary prostate cancers.

Mutation of this gene in tumor cells eliminates the cell-cycle blocking activity of p21.

Front 377

377. HNPCC

Back 377

Patients born with one defective copy of one of several DNA repair genes involved in mismatch repair.

They develop carcinomas of the cecum or proximal colon without an adenomatous polyp pre-neoplastic stage.

Loss of the normal "spell checker" function of the mismatch repair enzymes leads to gradual accumulation of errors in multiple genes including protooncogenes and tumor suppressor genes.

Front 378

378. How can mismatch repair mutations be documented?

Back 378

Mismatch repair mutations can be readily documented by examining microsatellite repeats (tandem repeats of 1-6 nucleotides that are fixed in normal tissues).

Variation of microsatellites is a hallmark of mismatch repair defects, such as those found in HNPCC.

Front 379

379. Xeroderma pigmentosum

Back 379

Patients develop skin cancers as a result of the mutagenic effects of UV light.

These patients have mutated nucleotide excision repair genes required for correcting UV light induced pyrimidine dimer formation.

Front 380

380. Inherited diseases with defects in DNA repair by homologous recombination

Back 380

This group of autosomal recessive disorder (Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia) is characterized by hypersensitivity to other DNA damaging agents.

In ataxia telangiectasia for example, ATM gene mutations result in a protein kinase that can no longer sense DNA double-stranded breaks.

Normally the ATM protein would phosphorylate p53 leading to cell cycle arrest or apoptosis; with defective ATM activity, DNA damaged cells continue to proliferate and are prone to transformation.

Front 381

381. BRCA1 and BRCA2

Back 381

About 5-10% of breast CAs are familial, and mutations in BRCA1 or 2 can account for 80% of such cases.

Individuals who inherit defective copies of BRCA1 are also at an increased risk of developing ovarian cancers, and those with germ line mutations of BRCA2 have an increased risk of ovarian cancer, male breast cancer, melanoma, and pancreatic carcinoma.

Front 382

382. Sustained angiogenesis

Back 382

Tumors induce angiogensesis by elaborating endothelial growth proteins such as vascular endothelium growth factor (VEGF) and basic fibroblast growth factor (bFGF).

The switch to an angiogenic phenotype in tumors may be associated with the loss of angiogenesis inhibitors (i.e. thrombospondin-1 which is normally induced by p53).