2. Oncogenes

Question 1

What is the role of oncogenes?

Answer 1

Promoting cellular proliferation. When activated, they promote uncontrolled growth and inhibit apoptosis

Question 2

How do point mutations activate oncogenes?

Give examples

Answer 2

Gain of function mutations –> hyperactive protein produced in normal amounts

RAS family receptor tyrosine kinases & BRAF have role in MAPK/ERK signalling pathway

Mutations –> constitutive activation of downstream GTP signalling

RAS commonly mutated in CRC, BRAF in melanoma

Question 3

How does amplification activate oncogenes?

Give examples

Answer 3

Increase in copy number of a gene, often associated with progression of cancer

HER2 in breast cancer (transmembrane tyrosine kinase receptor, EGF family)

MYCN transcription factor in late stage neuroblastoma

Question 4

How can translocation activate oncogenes?

Give examples

Answer 4

1. Creates novel fusion gene e.g. BCR-ABL in CML
2. Translocation into transcriptionally active region e.g. Burkitt lymphoma, MYC oncogene translocated into IG locus –> hig expression

Question 5

Give an example of insertional mutagenesis activating an oncogene

Answer 5

Viral DNA inserted near oncogenes –> aberrant activation –> cellular proliferation

E.g. Hep B in hepatocellular carcinoma

Question 6

Give an example of secreted growth factors as oncogenes

Answer 6

SIS - mutated form of platelet derived growth factor (PDGF). Overexpression –> transformation of fibroblasts with PDGF receptors –> unregulated cell growth

Question 7

What do growth factor receptors do?

Give an example of a growth receptor oncogene

Answer 7

Transduce signals for cell growth and proliferation

GoF mutations in EGFR in NSCLC cause increased tyrosine kinase activity of receptor –> cell proliferation

Treated with TKIs but acquired resistance due to Thr790Met