Cancer and Neoplastic Diseases

Question 1

Cause of Cancer

Answer 1

Progressive accumulations of genetic alterations lead to progression to tumor/cancer

Question 2

Somatic Gene Alterations (3)

Answer 2

Occurs randomly in somatic cells
Cause cancer in any cell
Not inherited

Question 3

Germline Gene Alterations (3)

Answer 3

Cause cancer susceptibility
Increased risk for specific cancers (cancer syndrome)
Inherited or de novo germline

Question 4

Two Hit Hypothesis of Tumor Suppressor Genes

Answer 4

1st Mutation: Inherited (susceptible carrier)

2nd Mutation or Loss of Other Gene Copy: Acquired - Loss of Heterozygosity leads to cancer

Question 5

Multistep Carcinogenesis

Answer 5

One mut in normal epithelium causes more to accumulate, progressing from epithelium -> adenoma stages -> carcinoma -> metastasis

Question 6

Protooncogenes

Answer 6

Normally promote cell growth and survival, but hypermorphic mut in one copy cause “gain of function” & turn into oncogenes

Question 7

3 Protogenes -> Oncogene Cancers (somatic or germline and description)

Answer 7

RAS Pathway Genes - somatic (pancreatic, colon)
Philadelphia Chromosome - somatic, FUSION of BCR and ABL genes
RET (RTK disease) - Somatic or germline

Question 8

Difference b/w Tumor Suppressor and DNA Repair Genes

Answer 8

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

Question 9

Recessivity of Tumor Suppressor/DNA Repair Genes/Cancers (description and final point)

Answer 9

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

Question 10

3 Molecular Bases for Cellular Aging/Death

Answer 10

Limited # of mitoses
Accumulation of muts through mitosis
Protein changes

Question 11

3 DNA Changes Causing Cellular Aging/Death

Answer 11

Chromosome instability
Telomere shortening
mt DNA muts

Question 12

2 Protein Changes Contributing to Cell Aging/Death (and notable point)

Answer 12

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

Question 13

Telomerase

Answer 13

Regenerates telomeres, so can be upregulated/overexpressed in tumors/cancer to cause immortality

Question 14

mt DNA Changes (3)

Answer 14

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

Question 15

2 Human Progeria Syndromes (onset, cause, & inheritance)

Answer 15

Werner Syndrome - adult onset, DNA helicase malfunction, AR

Hutchinson-Gilford Progeria - childhood onset, LMNA gene mut, de novo dominant

Question 16

Most Common Malignant Disease in Childhood

Answer 16

Acute lymphoblastic leukemia

Question 17

RB1 Gene (3)

Answer 17

Prototype tumor suppressor, "two hit" gene
Germline mut (followed by 2nd hit) causes retinoblastoma
Most de novo but can be AD w/ reduced penetrance

Question 18

5 Characteristics of Hereditary Cancer Syndromes

Answer 18

Multiple affected relatives over multiple generations
Early age of onset
Bilateral tumors in paired organs
Multiple primaries in 1 individual
Rare cancers

Question 19

Majority Cause of Breast Cancer

Answer 19

Just sporadic cancer, NOT single gene dominant high risk muts

Question 20

Most Common Genes Predisposing to Breast Cancer

Answer 20

BRCA1 or 2 make up about 50% of hereditary breast cancer

Question 21

Common Classifications for BRCA1 and 2

Answer 21

BRCA1 usually trip neg

2 usually ER+

Question 22

Ashkenazi Jews and BRCA Testing (2)

Answer 22

Very common, like 1/40

MUCH easier to test for bc almost all have 1 of 3 founder muts

Question 23

BRCA Testing in Non-Founder Populations

Answer 23

Find mut in youngest onset family member w/ breast cancer and test for that mut in other family members

Question 24

BRCA and Other Cancer Risks (4)

Answer 24

Doesn’t really increase recurrence risk, moreso new primary so contralateral increases
Aggressive ovarian cancer
Male breast cancer
Prostate cancer

Question 25

Tamoxifen

Answer 25

Chemoprevention (NOT chemotherapy) for breast cancer, ER modulatory so works on ER+

Question 26

Li Fraumeni Syndrome (cause & effect)

Answer 26

p53 tumor suppressor mut “guardian of the genome)

Very high penetrance at very early ages of a lot of rare/serious cancers (including breast)

Question 27

Peutz-Jeghers Syndrome (3)

Answer 27

STK11 gene mut, tumor suppressor
Hereditary BC syndrome w/ a lot of other cancers
Always has characteristic hamartomas & pigmentation

Question 28

Familial Adenomatous Polyposis (FAP) (4)

Answer 28

“Carpet” of >100 polyps
100% risk of colorectal cancer untreated
Prophylactic colectomy when polyp burden too large
Affects APC tumor suppressor gene

Question 29

AFAP

Answer 29

Attenuated FAP, has later onset and fewer adenomas

Question 30

MUTYH-Associated Polyposis: MAP (3)

Answer 30

Differential diagnosis of FAP, similar phenotype but instead caused by muts in DNA damage repair MUTYH gene
**Autosomal recessive

Question 31

Lynch Syndrome (3)

Answer 31

3% of colon cancer
Early age of polyp onset, usually in ascending colon
Also has extracolonic cancers like endometrium/ovary

Question 32

Amderstam II Criteria for Lynch Syndrome (3 criteria + 1 extra point)

Answer 32

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)

Question 33

2 Tests for Lynch Syndrome

Answer 33

Microsatellite Instability (from slippage on repeats)
Immunohistochemistry for MLH1, PMS2, and MSH2/MSH6 absence

Question 34

Difference in Ovarian Cancers from Colon and Breast Syndromes

Answer 34

Colon - usually low grade tumors

Breast - usually aggressive