M1 Genetics: Cancer

Front 1

There are two frameworks when thinking of cancer:
cancer as a [ genetic / hereditary ] disease where we're talking about all cancers and cancer as [ genetic / hereditary ] disease where we're talking about 5-10% of cancers.

Back 1

Genetic = all
Hereditary = 5-10% subset

Front 2

Fundamentally, cancer is a process of unregulated cell division. Expression or silencing of genes can contribute to three processes that are critical to cancer development: ___________ ( cell division) , ________ (stable cell cycle arrest), ________ (apoptosis).

Back 2

growth = cell division
senescence = stable cell cycle arrest
apoptosis = programmed cell death

These are all not inherently bad in and of themselves but its when the timing of these go haywire that stuff goes wrong.

Front 3

Describe the three categories of "cancer genes":

A. proto-oncogenes
B. tumor suppressor genes
C. repair genes

Back 3

A. genes that normally function to promote cell growth that go haywire (like growth factors or signal transduction molecules gone wild)
B. tumor supressor genes are genes that normally function to inhibit cell growth. When these lose their function, you lose your "gatekeeper genes".
C. Loss of repair genes loses the correction function.

Front 4

Which one of the following is not a proto-oncogene?
A. Cyclin
B. growth factors
C. P53

Back 4

C. P53 is a tumor suppressor gene

Front 5

_______ are abundant in cytoplasm. Their abundance is increased prior to the growth stage, and their abundance is lessened before senesence. These would be considered proto-oncogenes because if this is activated incorrectly, they activate the cancer causing potential.

Back 5

Cyclin and Cyclin-Dependent Kinase

Front 6

True or False:

CDK Inhibitor is a proto-oncogene.

Back 6

False. It is a tumor suppressor gene.

Front 7

Which one of the following is NOT a tumor suppressor gene?
A. P53
B. RB gene
C. CDK Inhibitor
D. check point genes
E. signal inhibitor molecules

Back 7

E. signal inhibitor molecules

Front 8

What commonly altered cancer gene is found to be mutated in ~50% of human tumors?

A. P53 gene
B. RB gene
C. P16 gene
D. CKI gene

Back 8

A. P53 gene . Germline mutations in P53 gene are responsible for much of the inherited cancer condition known as Li-Fraumeni syndrome. P53 is a transcription Factor and has DNA binding properties. It activates a CDK Inhibitor. If both copies of P53 are nonfunctional due to mutations, this removes the "brakes" and can lead to loss of cell cycle control at the G1/S control point and thus cancerous growth.

Front 9

Germline mutations in _____ gene are responsible for much of the inherited cancer condition known as Li-Fraumeni syndrome. This gene is a transcription factor and has DNA binding properties. It activates a CDK Inhibitor. If both copies of this gene are nonfunctional due to mutations, this removes the "brakes" and can lead to loss of cell cycle control at the G1/S control point and thus cancerous growth.

Back 9

P 53 gene

Front 10

True or False:

When the RB gene is phosphorylated by a CDK, it releases its hold on a transcription factor (E2F) which is then able to promote cell growth.

Back 10

True. RB is a tumor suppressor gene. If it is abnormally constantly phosphorylated, uncontrolled growth may occur.

Front 11

How can apoptosis be distinguished from necrotic cell death due to acute cell injury?

(hint: Necrotic cell death is typified by rapid....)

Back 11

cell swelling and lysis.

Pro-apoptotic protease activation, on the other hand, results in cytoskeletal disruption, cell shrinkage, membrane blebbing, and DNA degradation.

Front 12

True or False:

IAP and caspases are important regulators of apoptosis.

Back 12

True. IAP (inhibitor of apoptosis) inhibit caspases. Caspases are a group of cystein proteases that cleaves proteins after an aspartate residue in the process of degrading cellular structural components like actin and gene regulation proteins.

Front 13

Would the loss of function (thru mutation or deletion) of a caspase promote cancer or inhibit cancer?

Back 13

Promote! Cancer and autoimmune disorders would be more likely since your means of apoptosing is gone.

Front 14

Name 2 disorders of cell accumulation that can occur due to inhibition of apoptosis and 2 that occur due to increased apoptosis.

Back 14

inhibition of apoptosis: cancer and autoimmune diseases

increased apoptosis: AIDs and neurodegenerative disorders like Alzheimers disease, Parkinsons disease and spinal muscular atrophy

Front 15

True or False:

Evaluating tumor tissues for microsatellite instability (MSI) could be an important screen for identifying hereditary colon cancer.

Back 15

True

remember, microsatellites are areas of chromosomes involving repeating base pair themes (ex. AGAGAGAGA...) that are at times subject to slippage during DNA replication.

Front 16

True or False:
Tumor suppressor genes act dominantly to cause cancer

Back 16

FALSE.... tumor suppressor genes act recessively! There are two alleles and even if one allele is a bit mutated, the normal allele should be making the good protein. TWO hits are necessary.

Front 17

True or False:

The presence of Microsatellite Instability (MSI) is a clue that there is a problem with DNA repair.

Back 17

True!

Front 18

How does telomerase contribute to continued growth?

Back 18

Telomerase adds the TTAGGG repeat to the ends of chromosomes to maintain sufficient length for continued growth. (If it weren't there, eventually the continued deletion of DNA after rounds of replication -since abt 35 bases are not replicated and not part of newly synthesized strand- senescence would occur.

Front 19

Cancer epigenetics refers to what? What are the two main types of epigenetic changes in cancer?

Back 19

Cancer epigenetics refers to changes in gene expression not due to changes in sequence. The two main types of epigenetic changes in cancer are methylation and histone modification. Methylation results in loss of expression of associated genes. In many cancers, global HYPOmethylation occurs. (The exception being hypermethylation of CG islands). Histone modifications might methylate (turn off) or acetylate (turn on) portions that might directly influence expression of cancer genes.

Front 20

Would you classify cyclins as proto-oncogenes? How about CDK Inhibitors/ CKIs?

Back 20

Activated cyclins typically promote cell growth so excess expression would make it a proto-oncogene. CKIs inhibit cyclin expression, so they would function as tumor suppressors.

Front 21

True or False:

Cancer genomics involves the idea of mapping the cancer genome for individuals to tailor their treatment.

Back 21

True, knowing about microsatellite instability helps do this.

Front 22

Would you characterize DNA repair genes as a proto-oncogene or a tumor suppressor gene?

Back 22

DNA repair fixes damage to the genetic code of proto-oncogenes tumor suppressor genes, or even other DNA repair genes that function normally to inhibit cancer. Thus, DNA repair genes act (indirectly) as tumor suppressor genes.

Front 23

Would you guess that mutations in proto-oncogenes act in a dominant or recessive manner during carcinognesis? How about tumor suppressor genes?

Back 23

Proto-oncogenes act in a dominant fashion; tumor suppressor genes act in a recessive fashion.

(For explanation, see pages 203-4 in syllabus.)

Front 24

Overall, the contribution of hereditary causes of cancer is about _____ with ______% strongly inherited in a mendelian pattern.

A. 1/3 ; 5-10%
B. 1/4 ; 1-5%
C. 1/3 ; 1-5%
D. 1/4 ; 5-10%

Back 24

A. 1/3 ; 5-10%

The other causes of cancer is diet and smoking and other. In reality, all cancer probably results from a combo of inherited and acquired genotoxic (DNA damaging) environmental factors.

Front 25

True or False:
In families with hereditary cancer, tumor suppressor genes act dominantly.

Back 25

TRUE. If you look at the two hit hypothesis, we had two chromosomes with two wild-type suppressor genes. But in hereditary cancers, every cell is already mutated with one hit. Thus, the risk for cancer acts like a dominant. Note: the RISK for cancer is inherited, not the cancer itself! Usually it is actually a multi-step genetic process.

Front 26

Which of the following is not true regarding individuals with more inherited factors for cancer:
A. more likely to inherit multiple cancers
B. more likely to develop cancer earlier in life
C. more likely to develop cancer
D. more likely to have tumor suppressor genes act recessively

Back 26

D. is false, b/c for families with hereditary cancer, tumor supproessor genes act dominantly since one is usually affected already. (Born with a "hit".)

Front 27

What are the key characteristics of ICS (inherited cancer susceptibility)?

Back 27

Younger-than-expected age at cancer diagnosis. Multiple primary cancers, or bilateral cancer in paired organs (kidneys, breasts). Familial clustering of cancer is also key.

Front 28

Regarding examples of ICS syndromes, which is usually due to inherited mutations in P53 that cause sarcomas, brain cancers, leukemias, breast cancer, lung cancer and childhood adrenocortical cancers?
A. Li-Fraumeni Syndrome
B. von Hippel-Lindau Syndrome
C. Lynch Syndrome

Back 28

A. Li-Fraumeni Syndrome

Front 29

Regarding examples of ICS syndromes, which can be manifested with ataxia or seizures as well as pancreatic or renal cysts and benign tumors, illustrating an important point that cancer might not be the presenting sign of an ICS syndrome.
A. Li-Fraumeni Syndrome
B. von Hippel-Lindau Syndrome
C. Lynch Syndrome

Back 29

B. von Hippel-Lindau Syndrome

Front 30

True or False:

In von Hippel-Lindau syndrome, inherited p53 mutation is likely and plays a key role in the symptoms.

Back 30

False. This is Li-Fraumeni syndrome.

In von Hippel-Lindau syndrome, the VHL gene ( a tumor suppressor gene) is commonly mutated.

Front 31

Which of the following are NOT classic criteria for Li-Fraumeni syndrome?
A. Bone/Soft tissue sarcoma diagnosed < 45 years old.
B. First degree relative with cancer diagnosed < 45 years old
C. First or second degree relative with cancer diagnosed < 45 years of age or sarcoma at any age
D. Diagnosed with secondary cancer < 45 years of age

Back 31

D. is not a classic clinical criteria though multiple cancers are common in Li-Fraumeni syndrome

Front 32

Regarding Lynch Syndrome, a type of ICS (Inherited Cancer Suceptibility), which of the following comprises the Amsterdam criteria?
A. 1 individual w/ colon cancer diagnosed < 50 yrs old
B. 2 successive generations w/ colon cancer
C. 3 relatives with colon cancer, with at least one individual being a first-degree relative of the other two.
D. 3 successive generations of colon cancer

Back 32

D. not 3, just 2.

Front 33

Which of the following is not a problem regarding Lynch Syndrome's Amsterdam criteria usage?
A. Other types of cancer is common as well
B. Sometimes patients have limited family size or information
C. Variable penetrance (60-80% only, unlike Li-Fraumeri where it was 90%)
D. colon cancer is usually diagnosed later in life compared to other cancers

Back 33

D. colon cancer is usually diagnosed later in life compared to other cancers.

Dunno if that's even true, but it definitely ain't one of the problems with Lynch Syndrome

Front 34

When it comes to molecular testing for hereditary cancer susceptibilities, DNA sequencing is a gold standard but what were the two limitations mentioned in class?

Back 34

False negatives - for large gene sequences, labs sequence exons. The first step in the sequencing process is amplifying exons via PCR but if a large deletion exists in an allele, PCR primers will only bind to the remaining non-mutated allele. Thus only the normal, and not the deleted, allele will be a amplified and sequenced.

Variants of uncertain significance- DNA sequencing may identify mutations with unknown clinical significance.

Front 35

This will be an increasing challenge as more and more research leads to smaller minute detail differentiation associations.

A. Clinical Validity
B. Clinical Utility
C. Analytical Validity
D. Analytical Utility

Back 35

B. Clinical Utility

Are you going to do something different based on this genetic test? What if the test detects 2% higher risk for a certain cancer? Would you recommend a surgical procedure? Prolly not. The test might be analytically valid, but in terms of what the results are interpreted to clinically and what you decide to do clinically- that’s what clinical utility is all about. This will be an increasing challenge as more and more research leads to smaller minute detail differentiation associations.

Front 36

What are some risks associated with genetic testing? (Name 2 of 5)

Back 36

1. Is it fully informative? (Sensitivity of test may be poor… a negative on one of those test may work like a false negative.)
2. Survivor guilt for families
3. Burden of knowledge without a cure
4. May or may not have good screening techniques (ie. Bone cancer, lung cancer because there isn’t really any screening we can do)
5. In 2008 the genetic non-discrimination act makes it illegal for health insurance companies to refuse giving you health insurance or drop premium based on a genetic test result and family cancer hereditary disease
6. Increased anxiety / worry