0611 - Genetics of Cancer - EG

Question 1

Explain the two-hit hypothesis.

Answer 1

The 2 mutations (one for each allele) are required in order for a cancer to arise. Therefore in hereditary only one mutation is required as there is already an inherited mutation in one allele. Acquired (somatic) mutations required two mutation events (one for each allele).

Question 2

Define a proto-oncogene.

Answer 2

a normal gene that can undergo mutation to become an oncogene

Question 3

Define loss of heterozygosity.

Answer 3

loss of an allele, either by somatic recombination, loss and duplication, or chromosome loss. Is NOT due to a mere local change (e.g. SNP or epigenetic) but due to a larger sequence change.

Question 4

What occurs in a retinoblastoma?

Answer 4

• Uncontrolled cellular division of a retinoblast cell (retinal progenitor cell), due to mutation of RB1 – one mutant allele inherited in 40% of cases (autosomal dominant). N: RB1 is unphosphorylated, controls the initiation of DNA synthesis (halts if required). RB1 is inactivated by phosphorylation, or lost by mutation, leading to uncontrolled initiation of DNA synthesis and cell proliferation.

Question 5

What is the guardian of the genome? How does it function N and in cancer?

Answer 5

p53. N: short half-life ~20mins; In normal cell division, p53 plays no role; p53 with DNA damage, cell cycle abnormalities or hypoxia, etc, p53 is activated to either halts cell cycle to allow time for DNA repair, or causes apoptosis of cell.Pathology: Somatic p53 mutations occur in multiple cancers - p53 becomes inactivated, deleted, or non-functional, will either lead to cell death or cancer.

Question 6

What occurs in chronic myelogenous leukaemia?

Answer 6

Rare cancer of increased WBCs, due to a chromosomal translocation – of ABL1 proto-oncogene N: found on chromosome 9 (where it is only expressed periodically), to 22 - moves ABL1 to the end of a gene in which it becomes expressed constantly.

Question 7

What are the genes most commonly implicated in breast and ovarian cancer?

Answer 7

BRCA1 and BRCA2Tumour suppressor genesOnly 20% of breast cancers are due to an inherited predisposition. But 2 fold increase if one first degree relative is affected, 10 fold if more than one