L60: Genetic Basis Of Development Of Cancer

Question 1

Factors contributing to cancer

Answer 1

• Random mutation during DNA replication
• Environmental factors
• Hereditary factors
  —> determinative tumour (+ve aERS: links to specific environmental and hereditary risk factors)

Question 2

Cancer happens because earlier mutations can

Answer 2

• Enhance overall mutation rate

- Enhance cell proliferation —> larger cell population —> ↑ probability of mutation

Question 3

Cancer due to Proliferation, enhanced by

Answer 3

1. Activation of proto-oncogenes —> promote cell proliferation
   - point mutation (hyperactive protein made in normal amounts)
   - small deletion/insertion
   - translocations
   - gene amplification (normal protein greatly overproduced)
   - viral integration
   - chromosome rearrangement (Burkitt’s lymphoma, Chronic myeloid lymphoma)
   - Gain-of-function
   - Mutation of one allele is enough
   E.g. EGFR, HRAS1 (abnormally active intracellular signaling protein —> cell proliferation in absence of growth factor), FOS
2. Mutation of tumour-suppressor gene: fail to suppress cell proliferation
   - missense mutations
   - nonsense mutation
   - deletion
   - chromosome loss
   - Loss-of-function
   - Both alleles are usually need to be inactivated
   E.g. RB, p16, p53 which inhibit cell cycle entry, APC gene in FAP

Question 4

Cancer due to failure in DNA repair

Answer 4

• ↑ mutation rate by mutating DNA repair genes (mutator genes) e.g. hMSH2, ATM, a kinase required for repairing DNA double-strand breaks, mutator gene in HNPCC (Lynch syndrome)
• Both alleles need to be inactivated

Question 5

Multistage model for development of colorectal cancer

Answer 5

Mutation of
APC gene (tumour suppressor gene, early stage)
—> KRAS (oncogene, intermediate and late stage)
—> 18q SMAD4 (tumour suppressor gene, intermediate and late)
—> p53 (tumour suppressor gene, late stage)
—> MSH2, MLH1 (mutator gene, involved in all stages)

Question 6

Development of cervical cancer

Answer 6

HPV (human papillomavirus) inactivate both p53 and RB pathways