Cancer and Neoplastic Diseases Flashcards
Cause of Cancer
Progressive accumulations of genetic alterations lead to progression to tumor/cancer
Somatic Gene Alterations (3)
Occurs randomly in somatic cells
Cause cancer in any cell
Not inherited
Germline Gene Alterations (3)
Cause cancer susceptibility
Increased risk for specific cancers (cancer syndrome)
Inherited or de novo germline
Two Hit Hypothesis of Tumor Suppressor Genes
1st Mutation: Inherited (susceptible carrier)
2nd Mutation or Loss of Other Gene Copy: Acquired - Loss of Heterozygosity leads to cancer
Multistep Carcinogenesis
One mut in normal epithelium causes more to accumulate, progressing from epithelium -> adenoma stages -> carcinoma -> metastasis
Protooncogenes
Normally promote cell growth and survival, but hypermorphic mut in one copy cause “gain of function” & turn into oncogenes
3 Protogenes -> Oncogene Cancers (somatic or germline and description)
RAS Pathway Genes - somatic (pancreatic, colon)
Philadelphia Chromosome - somatic, FUSION of BCR and ABL genes
RET (RTK disease) - Somatic or germline
Difference b/w Tumor Suppressor and DNA Repair Genes
Tumor Suppressors are gatekeepers, they halt the cells if things are messed up, so w/ mut cancer will just keep dividing no matter how messed up it gets
DNA Repair genes fix muts, so more and more will just accumulate if damaged
Recessivity of Tumor Suppressor/DNA Repair Genes/Cancers (description and final point)
Recessive oncogenes at cellular level bc the other copy can cover if it’s messed up, but autosomal dominant inheritance for cancer susceptibility because at some point the second hit WILL happen somatically, causing cancer
- High but incomplete penetrance
3 Molecular Bases for Cellular Aging/Death
Limited # of mitoses
Accumulation of muts through mitosis
Protein changes
3 DNA Changes Causing Cellular Aging/Death
Chromosome instability
Telomere shortening
mt DNA muts
2 Protein Changes Contributing to Cell Aging/Death (and notable point)
Free radicals disrupt structure/function of prots
Glycosylation of proteins creates advanced glycosylation end products (AGEs) which cause artherosclerosis and cataracts and shit
Together May explain low calorie effect on longevity
Telomerase
Regenerates telomeres, so can be upregulated/overexpressed in tumors/cancer to cause immortality
mt DNA Changes (3)
Responsible for phenotypic features of aging
mtDNA lack DNA repair enzymes
Rate 100-1000x higher than nuclear DNA
mtDNA preferred target of free radicals and absence of histones
2 Human Progeria Syndromes (onset, cause, & inheritance)
Werner Syndrome - adult onset, DNA helicase malfunction, AR
Hutchinson-Gilford Progeria - childhood onset, LMNA gene mut, de novo dominant
Most Common Malignant Disease in Childhood
Acute lymphoblastic leukemia
RB1 Gene (3)
Prototype tumor suppressor, "two hit" gene Germline mut (followed by 2nd hit) causes retinoblastoma Most de novo but can be AD w/ reduced penetrance
5 Characteristics of Hereditary Cancer Syndromes
Multiple affected relatives over multiple generations Early age of onset Bilateral tumors in paired organs Multiple primaries in 1 individual Rare cancers
Majority Cause of Breast Cancer
Just sporadic cancer, NOT single gene dominant high risk muts
Most Common Genes Predisposing to Breast Cancer
BRCA1 or 2 make up about 50% of hereditary breast cancer
Common Classifications for BRCA1 and 2
BRCA1 usually trip neg
2 usually ER+
Ashkenazi Jews and BRCA Testing (2)
Very common, like 1/40
MUCH easier to test for bc almost all have 1 of 3 founder muts
BRCA Testing in Non-Founder Populations
Find mut in youngest onset family member w/ breast cancer and test for that mut in other family members
BRCA and Other Cancer Risks (4)
Doesn’t really increase recurrence risk, moreso new primary so contralateral increases
Aggressive ovarian cancer
Male breast cancer
Prostate cancer
Tamoxifen
Chemoprevention (NOT chemotherapy) for breast cancer, ER modulatory so works on ER+
Li Fraumeni Syndrome (cause & effect)
p53 tumor suppressor mut “guardian of the genome)
Very high penetrance at very early ages of a lot of rare/serious cancers (including breast)
Peutz-Jeghers Syndrome (3)
STK11 gene mut, tumor suppressor
Hereditary BC syndrome w/ a lot of other cancers
Always has characteristic hamartomas & pigmentation
Familial Adenomatous Polyposis (FAP) (4)
“Carpet” of >100 polyps
100% risk of colorectal cancer untreated
Prophylactic colectomy when polyp burden too large
Affects APC tumor suppressor gene
AFAP
Attenuated FAP, has later onset and fewer adenomas
MUTYH-Associated Polyposis: MAP (3)
Differential diagnosis of FAP, similar phenotype but instead caused by muts in DNA damage repair MUTYH gene
**Autosomal recessive
Lynch Syndrome (3)
3% of colon cancer
Early age of polyp onset, usually in ascending colon
Also has extracolonic cancers like endometrium/ovary
Amderstam II Criteria for Lynch Syndrome (3 criteria + 1 extra point)
At least 3 family members w/ LS cancer; one must be 1st deg relative of other 2
Two successive generations affected
One diagnosis <50
(FAP excluded)
2 Tests for Lynch Syndrome
Microsatellite Instability (from slippage on repeats) Immunohistochemistry for MLH1, PMS2, and MSH2/MSH6 absence
Difference in Ovarian Cancers from Colon and Breast Syndromes
Colon - usually low grade tumors
Breast - usually aggressive
