Tumor Suppressor Genes and the Two Hit Model

Question 1

What is the TSR gene controlling cell cycle that is mutated in retinoblastoma?

Answer 1

RB1

Question 2

What is the TSR gene controlling cell cycle that is mutated in neurofibromatosis type 1?

Answer 2

NF1

Question 3

What are the TSR genes controlling DNA repair that are mutated in lynch syndrome?

Answer 3

MLH1, MSH2, MSH6, and PMS2

sporadic- colon cancers

Question 4

What are the TSR genes controlling DNA repair that are mutated in breast cancer?

Answer 4

BRCA1/2

Question 5

What are the TSR genes controlling apoptosis that are mutated in Li-Fraumini syndrome?

Answer 5

TP53

Question 6

T or F. Loss of activity in BOTH TSRs of a gene are needed for cancer development

Answer 6

T. There are many mechanisms for loss of function

Question 7

Note that the loss of function mutations common in hereditary cancers is also the cause of many sporadic cancers. BUT they are acquired mutations and are not present in the germline or all the somatic cells and there is no hereditary risk

Answer 7

Note that the loss of function mutations common in hereditary cancers is also the cause of many sporadic cancers. BUT they are acquired mutations and are not present in the germline or all the somatic cells and there is no hereditary risk

Question 8

In all patients with retinoblastoma, what percent of patients are sporadic and hereditary?

Answer 8

sporadic-60%

hereditary-40%

Question 9

What happens to the RB1 gene alleles in sporadically acquired retinoblastoma?

Answer 9

they both ACQUIRE loss of mutations (i.e. both parents would be normal). Need both to cause cancer.

Question 10

What happens to the RB1 gene alleles in hereditary retinoblastoma?

Answer 10

first hit is inherited and is present in every cell in the body (constitutional heterozygosity for an RB mutation). This increases the risk for the second hit.

second hit is an acquired mutation in the other allele and is the founder that forms the tumor

Question 11

What are some common causes of the second hit in hereditary cancer?

Answer 11

1) point mutation (common cause of first hit)

*****2) Loss of Heterozygosity (any mutation giving rise to either hemizygosity- only one copy- or homozygosity)

• deletion (any size from large chromosome deletion to small micro deletion)
• mitotic nondisjunction
• mitotic recombination

3) Epigenetic silencing (normal allele becomes methylated and turned off)

In each scenario, there was one active allele that has been rendered nonfunctional, resulting in loss of function

Question 12

What are some characteristics of hereditary cancer?

Answer 12

1) multiple affected family members
2) Risk of multiple primary tumors
3) Increased risk of other types of cancers (for ex, for retinoblastoma it’s osteosarcoma and melanoma)
4) Early onset of onset
5) There may be other phenotypic features in addition to cancer
6) reduced penetrance