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241 Cards in this Set

  • Front
  • Back
Genetic damage:
Can lead to Increased transcription, on all the time,
Chromosomal genetic defects
Entire chromosomal deletions/additions, translocations
Or, can have addition/deletion of an entire chromosome.
Translocation
Error in meiosis/crossover - can disrupt the middle of a gene or the transcription sequence can be lost - applying to a dfferent gent
Mutations
Nucleotide Insertion/ deletion, point mutation
Cell division leads to more copies of gene
Gene amplification - ultra metabolizers, extra p450 patients hard to dose
Detection methods of genetic defects
How they work, when to use - different resolutions - cytogenetics, FISH, molecular
Look at bands
"That's chromosme 1 but this tail came from 13"
How to compare karyotype
Scissors and a glue stick (now still same only digital.)
Molecular detection (genetic)
Highest resolution - single mutations, small insertions, deletions
PCR:
Method of amplifying nucleic acid with enzymes and temperature cycling to make more copies. Is higest resolution for finding a sequence. In molecular genetic detection
Sequencing
Cheaper and easier than it used to be
Extra copy of chromosome 21
downs
Monosomies
do not survive
Cystic fibrosis
Recessive disease - need a defect in both alleles. Defect in chloride channel leading to abnormal secretions - lung pancreas, male sterility
CF
Some private OB practices will screen for common mutations. PCR screens for most common
57 isoforms?
Given same dose of coumadin, one may bleed.
P450 Matabolism differences; major bleeding events
Molecular pathology
Application of the techniques of molecular biology to the study for disease
Pathology
Study of disease
Pharmacogenomic pathology
Molecular, stil trying to study disease
Human disease determination?
Genetic, environment, both (most common) - obesity, cancer, diabetes
3 Categories of genetic disorder
Single gene defect (simplistic, but not common), ploydenic/multifactorial (obesity, cancer, diabetes), chromosomal
Chromosomal/cytogenetic
Chromosomal disorders
Germ line or somatic (mosaic, death or cell, neoplasia - but not passed on)
Germ line
Sperm has extra chromosome 21
Somatic embryonic
Mosaic, happens to only some cells
An individual's genetic defects can be
Inherited or acquired
Ways to inherit
Autosomal … (4 types)
Acquired genetic alterations
Not from parents, not passed on
A gene is turned on how?
Transcription factor binding to upstream regulatory sequences
What do you get when a gene is transcribe?
mRNA with poly-A tail (normal!)
Absent gene product, abnormalgene prodcut, gener regulation disorder (on/off all the time)
Upstream regulatory sequences
Every gene
Culture of cells to gest genetic
Cytogenetics, e.x Downs syndrome on child or fetus (amniocentesis)
Cytogenetic technique
Obtain cells, Culture, synch division, stop division in metaphase when tightly coil -(condensed), squash, stain, pair bands and look for differences from normal (alters from predictable banding)
When stopping cell division for cytogenesis, what do you do?
Stop in metaphase, using colchicine
Gene alteration leading to absence of product
Ex: stop codon
Genetic damage:
Can lead to altered product
Heritable disease
Got it from parents - might be able to treat/correct - pku
Genetic counseling
Diagnosis esp important to conduct prenatal counseling
Cystic fibrosis
Common chromosomal abnormalities
Downs trisomy 21
Downs
Related to maternal age, most common chromosomal disorder, facial:epicanthic folds - flat profile, retardation, increased Alzheimers and leukemia risk, cardiac other congenital
Tumors
Malignant transformation of a single somatic cell - dividing incorrectly and daughter cells have same change
Molecular diagnostic to cancer
Classify, diagnose, by PCR see if still there or coming back
Infectious disease genetics
Now we're testing for something that's not us.
Conserved sequence testing
Testing?
Bacterial meningitis - give antibiotics before you know - still find nucleic acid if org is dead
New medicine
Required genetic testing - severe rxn, metabolism dosing, adverse reactions
Matabolism of anticancer agents
Tight therapeutic window, polymorphism
Applications for molecular testing of infectious disease
Melting curve at which a dsDNA strand comes aparth is very specific to its sequence - related to G-C content
More use of genetics before therapy - pharmacogenomics - testing before prescribing
On translocation, may have disruption in the middle of a gene, turns on the wrong gene
SNPs and pharmacogenomics
Summary
Vysis sells screening kits for FISH of Downs, sex
What genetic damages cause disease?
The Plasias
Hyper - lots (Ex: lactation); Meta - change (GERD esophagus change to underlying type, Dysplasia is disordered growth; Anaplasia;Neoplasia
Hyperplasia
Breast Many more cells per ductile structure
Pre-neoplasia = dysplasia
Disordered growth; Pre-malignant epithelial changes in the cell
Dog his dysplasia
Not pre-neoplastic, disordered___
Malignant breast tissue picture - Can be well differentiated or poorly differentiated.
How closely does it look like the cells around it - the more deranged it gets..
Benign tumor margins
Well circumscribed, encapsulated
Malignant tumor margins
Invasive fingers, poorly circumscribed
Tumor absolutes:
benign tumors do not metastasize and do not invade.
Malignancies spread
Vascular, lymphatic, ex: normal colon cell won't travel, usually it has gotten pretty bad before cells have these skills
Identifying traveled malignancy
Tough, just have to match in loocks or do molecular testing
Will a cell matastasize
No molecular or visual way to tell whether cell will metastasize.
Which cells likely to metastasize
Larger, more anaplastic ones have most potential, but not predictable.
Metastasis
One little cell traveled and started to grow.
Degree of differentiation
These features aren't absolute, but still useful.
Benign/malignant cytological characteristics
Benign/malignant cytological characteristics - Nuclei
Regular/irreg shape & size
Benign/malignant cytological characteristics - Cytoplasm development
Well developed/variable
Nucleoli
Distribution of chromatie
Monster cells
The right slide doesn't look like anything normal, divide but don't separate
Seminoma
Testicular cell carcinoma
Hepatoma
Now hepatocellular carcinoma
Lymphomas
Solid tumors that are neoplastic collections of hematopoeitic cells
Leukemias
When neloplastic hematopoeitic cells circulate
Neoplasia
"new growth" abnormal, exceeds normal tissue growth, uncoordinated, persists despite regulation
Oncology
Oncos = tumor
Cancer
Malignant tumor - extend into other tissue - like claws
Tumor
"swelling" usually neoplastic
Metaplasia
Barrett's esophagus, lung
Neoplasia
Autonomous excessive growth not coordinated with the tissues around it = Pictures of breast (benign & malignant)
Degree of differentiation
Benign tend to be welldifferentiated, resembling the tissue of origin.
Benign/malignant cell growth cycle
Malignant grow faster, vary within self
Leiomyoma
Benign uterine tumor, tissue look like smooth muscle still
Benign naming
-oma
Malignant naming
Add tp cell of origin (carcinoma - epithelial)/ (sarcoma - mesenchymal)
Sarcoma
Malignant neoplasm derive from mesenchmal tissue (muscle, bone, nerve)
Carcinoma
Malignant neoplasm of epithelial origin (adenocarcinoma)
Lymphoma
Malignant neoplasm of hematopoietic cell ofigin (eg b cells)
Nomenclature
Adipose
cartilage
Smooth muschle
Striated muscle
gland
Adenoma/adenocarcinoma
squamous
papilloma
Menchymal origin
Epithelial origin
Papilloma/squamous cell carcinoma
Why name tumors?
Id, treat, prognosis
Staging vs. grading
Stagin more predictive
TNM
T:size; N:regional lymph node involvement; M=distant metastases
Prostate staging
t/1-4/a-c, n0-n3; m0-1
Other than prostate
Some grading not very specific - well/mod/poorly differentiated
Local features of neoplasia
Destruct vital structure; obstruction; ulceration; necrosis and bleeding
Loss of integrity
Bone fracture
GI tract tumor
Grows and obstructs
Systemic features of neoplasia
Anorexia (cachexia), weigh loss fever, anemia decreased resistance to infection
Paraneoplastic syndromes
Symptoms that are explained by products of the tumor (eg creating hormones, cushing's syndrom due to cortisol when made by lung - nt usually made by lung)
Neoplasia/cancer
Not a single disease - highly variable
Neoplasias manifest
Variably, may present with different symptoms
Immune status of host, histologic grade, location, sensitivity of tumor cells to therapy
Anaplasia - the worst differentiation a cell can have. Seen in tumors, May have to stain for protein markers to see where it came from. Not identifiable as to where it cam from
Anaplasia is not in "the sequence"
Barrett's esophagus pictures - metaplasia led to dysplasia and to adenocarcinoma. Different arrangement of cells.
Benign and malignant included in "neoplasia" - and all are autonomous (ignore growth factors); excessive, disorganized
Benign v. Malignant: growth, metastases, capsule, nnecrosis, hemorrhage, differentiation, nuclei, mitoses
Breast cancer progression pictures. Not all of these progress. For instance, breast hyperplasia can come & Go.
Characteristics of Malignancy
Invasion metastasis
Benign tumors still expand /invade into other tissues - usually means benign ones are encapuslates and have well defined margins
Differences in size and shape of cell. Neuceloli are off to the side, some extremely large "monster" cells.
Impingment - Benign, but still fatal. Can't put that much pressure on brain
Melanoma has just kept name but is highly malignant
Metaplasia is not pre-neoplastic, but could lead there. Dysplasia is pre-neoplastic process
Necrosis due to too fast growth where they outgrow their blood supply.
PICS Thinks salivary gland tumor / oncocytic tumor in the kidney benign look benign
Plasias all reversible except neoplasia
Pleo-many morph-shapes
Prostate diagram showing various differentiation
The deeper a tumor spreads into tissue layers, the more likely it has access to vascular components to spread. (worse prognosis) T goes up.
Genetic hypothesis of neoplasia
Multiple damage (mutations, lead to cell death or disruption in regulation
Neoplasms are accumulations of genetic events
Alter cell regulation
Ase we age, the is more chance for the spontaneous damage
More replication,
Not just any genetic damage
- cell cycle abnormalities in one of the (many) regulatory factors (remember excessive uncontrolled autonomous growth?)
Steps in cell proliferation:These are all different places where something can go wrong.
Growth factor binds to receptor; receptor temp activated; signalling activiated, binds to DNA to turn on growth factors SEE LIST
The kind of genes that can be damaged and lead to neoplasia.
Proto-oncogenes;
GGW: Protooncogene
EX: maybe normal for fetal development but shut off - mutation turns it back on
GGW: Recessive oncogenes
Inhibitory factors ("the brakes") when go out lose control
GGW: Genes that regulate programmed cell death
Apoptosis - things live when they should not
GGW: repair
Damage to DNA repair genes
Over 90% of tumors have telomerase wrong
this as one of the things wrong - it's able to turon on telomerase.
Sustained antiogenesis
Tumors have to feed themselves or they can't grow. You don't have normal arteriole or venous capillary bedys. Realy important for tumor growth
Cell migration
Ability to metstasize requires collagenase, etc to get out and let go of neighbors
Molecular basis of neoplasia
Explains tumor cell behavior, influenc of geography, culture, environment, age, heredity
Why cells become neoplastic?
Genetic damage, maybe hereditary, lead to instability, lead to further instability
Cell division/DNA replication
Highly regulated, stops when proliferation no longer needed (liver regeneration, heal skin/ colon disease can cause sloughing and regenerates perfectly)
Differentiation
Specialized function is normal, when see changes in differentiation indiactes
Cell cycle
A simplistic circle not real - in reality is a complex and redundant system that regulates - it takes multiple changes to accumulate and lead to neoplasm
Carcinogenesis
Multi-step process, different for everyone even if have the same organ
Single mutation
Cannot fully transform a cell to neoplasm , most cancers involve several oncogenes and loss of 2 or more suppressor genes
Gene expression
Look for a pattern of changes to asses prognosis - what patterns are associated with different behavior in patients? Moving toward real patient care.
protein profiles
What is being produced by genes that indicates pattern of neoplastic behavior
Dysregulation categories - growth
Growth factors changes binding kinetics; GF receptor (common); transduction proteins, nuclear regulatory proteins, cell-cycle regulator
Inhibitory dyregulation categories
Insensitive to growth-inhibitory signals (nuclear reg proteins, transcrip factors, other); evasion of apoptosis
BCL2/p53
Balance between living/apoptosis; if BCL2 is overexpressed the too many cells escape apoptosis; if p53 is damaged not enough apoptosis occurs
DNA repair defect
If inherited - genomic instability syndromes; NER repair of UV induced cross linking - without it suscept to skin cancer
An example of a common sequence in breast cancer, not always the same
Progress toward dysplasia, multi-steps to neoplasia
Pancreatic cancer sequence
Telomere shortening, K-RAS, p16, p53 - one example of path to invasive carcinoma
Colon cancer sample pat
Normal, inherited predisposition, many other change, then p53, then telomeras, many genes.
P53
Proapoptotic but also other regulation in cell cycle
Tumor suppression gene
Usually recessive, so when one allele fails can develop cancer
Generalized diagram with timeline of cancers
Skin cancer might have change at age 15; bladder cancer 20 years;
Think of odds of cancer
Damage, slips through repair, happens to be one of the genes impt to regulation, AND need to have multiple of these damaging events
Ulcerative colitis
Flat areas of dysplasia lead to cancer, sometimes have colon removed
These genes aren't normally turned on - shut down after angiogenesis. These types of alteratations are harder to cure.
Growth factor binds to receptor; receptor temp activated; signalling activiated, binds to DNA to turn on growth factors SEE LIST
this as one of the things wrong - it's able to turon on telomerase.
Molecular basis of neoplasia - unifying concept
Tumor cell behavior; influend of G C E A H
Genetic hypothesis of neoplasia
GROUP of disorders to REGULATORY geneswhich alter normal replication. Incl: chromosomal brakage, translocation, point mutation
Sonpaneous, environmen, familial
Incidence
New cases in a specific period, &population
Prevalence
All cases
Bad stuff in environment
Sunlight, inhaled carcinogens, hot dogs, etc
Radiation
UV exposure every day: melanoma (aggressive); squamous cell carcinoma, basa call carcinoma
X-ray exposure
Chernoble, factory: leukemia, thyroid, breast, colonic
Chemicals/toxins
Cigaretts-squamous cell carcinoma of lung plus other areas where some goes
Asbestos
mesothelioma
Aflatoxin
Hepatocellular
Know that radiaition
Causes cancer
Alcohol
Hepatocellular carcinoma
Virus leads to cancer
Integration of viral DNA can cause genetic damage - separate from regulatory sequence
Chronic injury/repair
Esp viral hepatitis C causes injured cells that need to be replicated/repaired - increase chance of an error
HPV
Infects skin/mucosal; low risk subtype leads to warts, high risk leads to sq cell carcinoma
Hepatitis B
Acute/chronic liver infection predisposes to hepatocellular carcinoma
EBV
Infects B cells, gives you mono, once you have it is for life, in some cells it can transform to lymphoma
Different areas of the world have different incidence of cancer
Cultural practice - smoked foods, etc Stomach cancer high in asia, low in US; lung cancer high in US
Stomach cancer
Associated with smoked fish
Breast/prostate cancer
Overfed populations
Lung
Who's smoking
Age:
Dna damage/repair ongoing, older people have more opportunity for damage, 55-75 is most deaths
Familial predisposition
Remember it's accumulation of damage - this is one strike against you. Colon cancer for same reason, but get at 25 instead of 55
Retinoblastoma
Inherited damaged RB gene, in eye of infants
Familial adenomatous polyposis of colon
See polyps at young age in colonoscopy - end up with prophylactic colectomy by age 30(?) 100% of these patients have cancer by age 30.
BRCA1; BRCA2
Prophylactic mastectomy debate
Understanding molecular basis of cancer
Helps diagnose, pick better chemotherapy; better take steps to prevent; screen better
Molecular techniques for dx
Classify, evaluate residual, monitor relapse, ident appropriate therapy
A particular molecular change
Might indicate one is going to do worse
Carcinogenesis
Result from single cell transformation, passed along
Cell cycle
Where to look for the change
CML
Has one characteristic change (has others thought) that defines it - Philadelphia chromosome - tyrosine kinase "on" all the time.
Phildelphia chromosome
In CML, Translocation detectable by cytogenetics, FISH, molecular methods
FISH
Shows CML where ABL and BCR are separated in one cell and together in another
Can specialize chemotherapy to be more specific
Gleevec
Tyrosine-kinase inhibitor for CML, also inhibits GIST - drug blocks TK that is on all the time
Herceptin
Ab blocks HER2-neu a growth factor receptor. Human Epidermal growth factor Receptor 2 HER2 - more receptors on cell surface
HER2
20-25% of breast cancer patients assoc with decreased survival, give Herceptin to make monoclonal Ab block the receptor
HER2 testing
Immunohistochemistry / FISH
Prevention
Earlier screenings, sunscrean for xeroder…., prophylactic colon removal (extreme)
Prevention avoidance
Radiation therapy, sun clothing
Physical carcinogen protection
Clothing sunscreen, radiation safety
Lifestyle
Smoking
Occupational health
Viral prevention
Safe sex, HPV vaccine, HPB vaccine and avoid exposure; HTLV-1 screen blood supply
Cancer screening
Identify premalignant lesions and/or early malignant lesions before they get big and behave badly
Pap smear
Screen for cervical carcinoma - cancer arises at transitionfrom inner/outer part of cervix; remove cels with brush; visually inspect for changes
Normal cervical cell picture
Cervical cancer pictures
Colon cancer screening
If see lesion, take it out; stalk occurs due to the way colon moves. No problem.
Incidence rates exclude skin; shows some more deadly - #s don't match
Safeguards against cancers
Molecular basis of neoplasia - unifying concept