Cancer Genetics

Question 1

Mechanisms of action of tumor suppressor genes

Answer 1

1. Regulate cell cycle
2. Regulate cell death
3. Repair DNA

Question 2

What are the hallmarks of a tumor suppressor gene?

Answer 2

1. Loss of wildtype protein in tumor cells
2. Germline mutations increase cancer susceptibility
3. Loss of gene in animal model should confer cancer-prone phenotype (p53 null mice develop lymphomas)

Question 3

Outcome of functional loss of a tumor suppressor depends upon _____ and _____

Answer 3

tissue / context

Question 4

Retinoblastoma (Rb)

Answer 4

Autosomal dominant

Ubiquitously expressed tumor suppressor

Question 5

How does Rb regulate cell cycle?

Answer 5

Binds E2F (transcription factor) —> represses E2F-dependent transcription of cell cycle genes

Question 6

What phosphorylates Rb?

Answer 6

CDKs

Question 7

What cancers can be caused by mutation of Rb?

Answer 7

Retinoblastoma
Small cell lung cancer
Osteosarcoma

Question 8

What cancers can be caused by phosphorylation of Rb?

Answer 8

Breast
Melanoma
Colon

Question 9

What cancers can be caused by viral oncoprotein associated with Rb?

Answer 9

Cervical

Question 10

DNA viruses can cause tumors via inactivation of which genes?

Answer 10

Rb and p53

Question 11

T/F: Wild-type p53 is present in tumor cells

Answer 11

False. Only mutant p53 has been found in tumor cells.

Question 12

Loss of wildtype p53 —> _____

Answer 12

Tumors

Question 13

What is the most frequently mutated gene in human cancers?

Answer 13

TP53

Question 14

What regulates p53?

Answer 14

MDM2 binds p53 and inactivates it

Question 15

Mechanisms of mutant p53 mutation

Answer 15

1. Bind DNA to alter gene expression
2. Bind to transcription factors to enhance their function
3. Form a complex with transcription factors to prevent their function
4. Interact with proteins to change their diversity

Question 16

Which tumor suppressor functions in adhesion and signaling?

Answer 16

APC

Question 17

What is one of the earliest events in colorectal cancer?

Answer 17

Loss of APC

Question 18

BRCA mutations result in what?

Answer 18

Truncated proteins

Question 19

How do mutations cause cancer?

Answer 19

They result in structural rearrangements of the protein so that the protein is continuously expressed (GAIN OF FUNCTION)

Question 20

Describe the Ras point mutation.

Answer 20

Point mutations cause Ras to become GAP-insensitive (aka Ras cannot bind GAP) –> Ras is constitutively active / GTP is constitutively bound

Question 21

What is gene amplification?

Answer 21

Expansion of gene copy number within the cell

Question 22

Where is gene amplification frequently seen?

Answer 22

c-myc and erbB-2 (HER2) –> amplified in breast and ovarian cancers

Question 23

Two mechanisms of chromosomal rearrangement

Answer 23

1. Transcriptional activation of proto-oncogenes

2. Creation of a fusion gene

Question 24

What is an example of transcriptional activation caused by chromosomal rearrangement?

Answer 24

c-myc translocations in Burkitt’s lymphoma

c-myc moved to locus of Ig heavy chain

Question 25

What is an example of a fusion gene caused by chromosomal rearrangement?

Answer 25

Philadelphia chromsome
c-abl gene (9) fused to bcr gene (22)
causes increased kinase activity and abnormal cellular localization

Question 26

Where are the majority of mutations in colorectal cancers found?

Answer 26

In three functional protein groups:

1. Cellular adhesion and motility (APC)
2. Signal transduction (APC)
3. Transcriptional regulation (Ras)

Question 27

Which defect is seen in 90% of colon cancers?

Answer 27

Ras defect