Cancer Genetics

Question 1

How does Retinoblastoma represent a “Two-Hit Model”?

Answer 1

Two types

- Bilateral: runs in families 
- Unilateral: appears sporadically- requires            two events in one cell

Question 2

What is the Inheritance Paradox?

Answer 2

Mutations appear to be dominant; but are actually recessive at a cellular level because it requires a second copy to be mutated.

Question 3

What is Loss of Heterozygosity (LOH)?

Answer 3

• Markers in different regions, Two forms each in normal cells, Missing markers indicate LOH, gives probable location of gene.

Question 4

Describe genetic features of Neurofibromatosis?

Answer 4

• Two different translocations in region, only 50 kb apart, interrupt same gene, structure suggested role in cancer.

Question 5

How many divisions does it take for normal cells to become senescent?

Answer 5

50-70 divisions

Question 6

What are some physical symptoms of Neurofibromatosis-1?
Where is the defect located?
What is the molecular result of the defect?

Answer 6

• Skin lesions, cafe au lait spots and possible larger tumors may develop.
• Dominant gene on chromosome 17 tumor suppressor gene
• Down-regulates RAS signaling

Question 7

• What gene codes for the p53 protein?

- What are some functions of the p53 gene?

Answer 7

• The TP53 gene
• Functions: 1) Binds to CDKN1A (p21) promoter
  2) Increases p21 level, inhibit cell cycle
  3) Senses DNA damage
  4) Directs cells to undergo apoptosis
  5) Interacts with PTEN and BAX

Question 8

What is the classic TP53 mutation?

Answer 8

• Li-Fraumeni syndrome
• Breast, colon and adrenocortical carcinomas
• Soft tissue sarcomas,
• Osteosarcomas
• Brain tumors
• Leukemia

Question 9

Contrast APC to HNPCC (general)?

Answer 9

APC (Familial Adenomatous Polyposis Coli), adenomas start as many polyps can progress to malignancy.
- HNPCC (Hereditary Non-polyposis colon cancer), many fewer polyps

Question 10

In APC what causes polyp formation? Approximately how many polyps form? What percentage of sporadic cases is the APC gene mutated in?

Answer 10

• Loss of second copy of APC gene
• 100s
• 85%

Question 11

What are the parts in the multi-step model of tumor progression?

Answer 11

• First hit is APC mutation (down regulates Beta-catenin, myc signals)
• K-Ras activation may follow (50%)
• TP53 mutations common later
• Other genes may be altered (SMAD4)

Question 12

In HNPC what is the percentage of penetrance in heterozygotes? What other gene mutations are most common?

Answer 12

• 70 - 90%

- Mutations in several genes such as MSH2 and MLH1 are most common (DNA mismatch repair)

Question 13

What is the correlation between number of polyps and malignancy rates?

Answer 13

Number of polyps increases odds of tumor.

Question 14

What two genes are implicated in breast cancer?
What are the percentages of occurance of breast cancer with family history vs. individual history?
- What does mutation increases breast cancer risk in men?

Answer 14

• BRCA1 and BRCA2
• Family history (20% increase), history of breast cancer and ovarian (60-80%)
• BRCA2

Question 15

What is the normal function of the BRCA gene?

Answer 15

• BRCA1 gets phosphorylated and binds to BRCA2, RAD51

Question 16

What percentage of familial melanoma may be due to familial form?

• What gene is linked in some familial melanoma?
• What is the function of p16 and in what percentage of familial melanomas are they mutated?

Answer 16

• 5-10%
• linked to CDKN2A
• p16 (CDK inhibitor) inhibits CDK4 and slow cell cycle, mutated in 25% of sporadic melanomas.

Question 17

What mutated gene is inherited in Multiple
Endocrine Neoplasia?
What mutation affects the receptor tyrosine kinase?

Answer 17

• MEN2 is inherited form - 3 subtypes

- RET gene mutated

Question 18

Are most cancers sporadic or inherited?

Answer 18

Sporadic