Tumor Suppressors- Lecture 55

Question 1

What syndromes have been identified to be associated with heritability?

Answer 1

familial retinoblastoma (pRb)
Wilms’ tumor
kidney cancer (WT1)
hereditary breast cancer (BRCA1 and BRCA2)
hereditary melanoma (p16, p15)
Li-Fraumeni syndrome (p53- note that this is a wide variety of cancers)

Question 2

The susceptibility to tumor formation is ______, but not all those who have inherited the defective gene get cancer. This is an example of ______.

Answer 2

Mendelian dominant

incomplete penitrance

Question 3

What distinguishes DNA tumor viruses from RNA tumor viruses?

Answer 3

DNA tumor viruses contain novel oncogenes within their genome that do not have a cellular counterpart

Question 4

Provide examples of DNA tumor viruses.

Answer 4

Simian virus 40 (express large T antigen that binds to both cellular p53 and Rb, inactivating their function)
Adenovirus (similar mechanism using E1A binding to pRb and E1b binding to p53)
Human Papilloma virus (expresses E7 inctivating pRb and E6 which target p53 for degradation)

Question 5

Describe the kinds of retinoblastoma.

Answer 5

Familial: kids present with two eyes affected and often get secondary osteoblastoma
Sporadic: presents in one eye only and no increased risk for secondary cancer
due to two Knudsen’s two-hit hypothesis the inherited mutant in the Rb allele predisposes kids to cancers

Question 6

Describe one important distinction between oncogenes and tumor suppressors.

Answer 6

activation of an oncogene is a “gain of function” which can arise from a single allele mutation
mutated tumor suppressors have a “loss of function” and require effects on both alleles

Question 7

Name the possible mechanisms for tumor suppressor loss in human cancers.

Answer 7

deletions
missence mutations
frameshift mutations

Question 8

Describe the pathway of mutated p53 and its role in tumor suppression inhibition.

Answer 8

mutations in p53 (commonly found in highly conserved domains) are most common in it’s “hotspots” (DNA binding regions or structural components for DNA articulation) which cause reduced protein degradation and increased stability because it can no longer interact with Mdm2 (its inhibitor) which is inhibited by ARF (which is upregulated by the activation of Myc, Ras, and E1a by oncogenes)

Question 9

Provide an example of a cancer syndrome associated with missense mutations in tumor suppressor genes.

Answer 9

Li Frumini syndrome (tumors of multiple kinds)

Question 10

Provide an example of a cancer syndrome associated with frameshift mutations in tumor suppressor genes.

Answer 10

Familial Adenomatous Polyposis

Question 11

Describe the pathway of mutated APC tumor suppressor on human cancer.

Answer 11

frameshift mutations in APC genes result in expression of trunctated proteins that no longer bind to beta-catenin (transcriptional regulation promoting cell proliferation) so it never gets phosphorylated and degraded and is continually active

Question 12

Provide an example of a tumor suppressor gene that is commonly deleted resulting in human cancer.

Answer 12

pRb

Question 13

What are the ways haplo-insufficiency can result in loss of tumor suppressor function?

Answer 13

reduced expression
dominant negative effect
transcriptional silencing

Question 14

Describe reduced expression.

Answer 14

mutation of only one allele

reduced level of expression drops below the expression threshold needed for full suppressive activity

Question 15

Describe dominant negative effect.

Answer 15

one allele is mutated but the mutant is expressed over the wild-type because it can still form a complex with the wild-type but the complex is not functional

Question 16

Describe transcriptional silencing of wild-type allele.

Answer 16

when one allele is inactivated by mutation and the remaining allele is silenced through some epigenetic means