Cancer Genetics

Question 1

Cancer

Answer 1

Uncontrolled cell proliferation, disease of cellular differentiation, normal growth and differentiation disrupted

Question 2

Genetic causes of cancer

Answer 2

Changes occur in genes that regulate proliferation, may be caused by mutagenic agents

Question 3

Environmental causes of cancer

Answer 3

Carcinogens can be environmental, cancer frequencies change with environment

Question 4

Inherited cancer

Answer 4

Mutations can occur in germline, inherited by subsequent generations, predisposes to cancer- one step on pathway to cancer

Question 5

Knudson’s two-hit model

Answer 5

Retinoblastoma- bilateral (runs in families), unilateral (appears sporadically), need two mutations for cancer, one copy bad already in inherited form, sporadic requires two events in one cell

Question 6

Tumor suppressor genes

Answer 6

Normally control cell cycle and proliferation, RB1, CDK inhibitors

Question 7

Oncogenes

Answer 7

Enhance cell proliferation when activated, few inherited mutations

Question 8

DNA repair genes

Answer 8

Help maintain integrity of genome, BRCA1, BRCA2, mismatch repair genes

Question 9

Inheritance paradox

Answer 9

Mutations appear to be dominant in inheritance pattern, are recessive at cellular level (require second copy to be mutated), truly dominant forms are lethal

Question 10

Mapping cancer genes

Answer 10

Tumor cells compared to normal cells, look for areas of consistent change, heterozygous loci are studied, lost markers indicate loss of heterozygosity (LOH) near gene of interest

Question 11

Loss of heterozygosity (LOH)

Answer 11

Markers in different regions, two forms each in normal cells, missing markers indicate LOH, give probable location of the gene

Question 12

Refining the gene map

Answer 12

Mutations in several families examined, narrow the region with linkage studies, look for anomalies in that region

Question 13

Refining of neurofibromatosis 1 (NF1) gene

Answer 13

Two different translocations in region, only 50 kb apart, interrupt the same gene, structure suggests role in cancer

Question 14

Chromosome considerations

Answer 14

Tumors often have abnormal chromosomes, aneuploidy, translocations, may contribute to tumor progression, may arise from mutations in DNA repair or cell cycle control genes, telomerase may be activated

Question 15

Telomerase and cancer

Answer 15

Maintain telomere length, prevent aging, normal cells become aged after 50-70 divisions, low telomerase activity means shortening of telomeres and limits on division, active telomerase means immortal cells

Question 16

Neurofibromatosis 1 (NF1)

Answer 16

Skin lesions, “cafe au lait spots”, large tumors may develop, dominant gene on chromosome 17, tumor suppressor, similar to GTPase activating protein (GAP), down-regulates RAS signaling

Question 17

TP53 gene

Answer 17

Codes for p53 protein, mutations found in over half of all tumors, loss of 17p in colon tumor cells common, small deletions localize to TP53 region, most are missense, mainly in DNA binding domain of protein

Question 18

p53 function

Answer 18

Binds to CDKN1A (p21) promoter, increases p21 level, inhibits cell cycle, involved in DNA damage sensing, directs damaged cells to undergo apoptosis, interacts with PTEN and BAX

Question 19

Action of p53

Answer 19

Transcription factor regulating cell cycle, DNA repair, and programmed death, p53 senses DNA damage (or hypoxia), halts the cell cycle so new DNA synthesis will not replicate the damaged DNA, up-regulates genes involved in DNA repair, stimulates apoptosis if damage is severe

Question 20

Li-Fraumeni syndrome

Answer 20

Inherited TP53 mutation, high frequency of a variety of cancers in families, many tissues show tumors- breast, colon, adrenocortical carcinomas, soft tissue sarcomas, osteosarcomas, brain tumors, leukemia

Question 21

Familial adenomatous polyposis coli

Answer 21

Familial colon cancer, gene termed APC, inhibits beta-catenin, adenomas start as polyps, can progress to malignancy

Question 22

Hereditary non-polyposis colon cancer

Answer 22

Familial colon cancer, disease termed HNPCC, many fewer polyps, other tumors common

Question 23

APC and colon cancer

Answer 23

Tumor suppressor gene, loss of second copy causes polyp formation, APC gene mutated in 85% of sporadic cases, loss not sufficient for cancer progression

Question 24

Multi-step model of cancer progression

Answer 24

First hit- APC mutation, down regulates beta-catenin, myc signal transduction, causes proliferation, early adenoma
Second- K-RAS activation, gain of function, signal transduction
Third- TP53 mutation common
Fourth- other genes altered, SMAD4, genes leading to metastasis

Question 25

HNPCC genes

Answer 25

1-5% of colorectal cancer, 70-90% penetrance in heterozygotes, other cancers fairly common, mutations in MSH2, MLH1 are most common, all involved in DNA mismatch repair, loss of function increases mutation rate

Question 26

APC vs. HNPCC

Answer 26

APC has more polyps, low probability of malignancy, number of polyps increases odds of tumor, HNPCC has few polyps, probability of further mutation high, increases probability of tumor progressing

Question 27

Breast cancer

Answer 27

BRCA1, BRCA2 account for 1-3% of cancers, family history increases to 20%, history of breast and ovarian cancer 60-80%, mutation increases lifetime risk, BRCA2 increases breast cancer risk in men

Question 28

BRCA gene function

Answer 28

Repairing double-stranded DNA breaks, BRCA1 phosphorylated, binds BRCA2, RAD51

Question 29

Familial melanoma

Answer 29

Risk increases with affected relative, 5-10% due to familial forms, some linked to CDKN2A, CDK inhibitor known as p16, inhibits CDK4 like p21, mutated in 25% of sporadic melanomas, CDK4 gain of function mutations also seen

Question 30

Multiple endocrine neoplasia (MEN)

Answer 30

MEN2 is inherited form (3 subtypes), RET gene mutated, receptor tyrosine kinase, activated one of few oncogenes that shows inherited cancer, each subtype shows characteristic mutations, loss of function mutations cause developmental anomalies

Question 31

Genes and common cancers

Answer 31

Most cancers are sporadic, not inherited, much familial clustering unexplained, increased risk is known, knowledge of cancer to identify pathways and alterations