19.06.02 oncogenes

Question 1

What is an oncogene

Answer 1

A gene that normally is involved in controlling cellular proliferation. When overactivated, leads to transformation of cells into tumour cells by promoting uncontrolled growth.

Question 2

5 ways to activate oncogenes

Answer 2

• point mutations
• gene amplifications
• chromosomal translocations
• Local DNA rearrangements (insertion, deletion, inversion, transposition).
• Insertional mutagenesis (insertion of viral DNA)

All gain of function

Question 3

5 classes of oncogene

Answer 3

• Secreted growth factors
• Growth factor receptors
• Signal transducers
• inhibitors of apoptosis
• Transcription factors

Question 4

Secreted growth factor class of oncogenes

Answer 4

• Constitutive activation contributes to malignant transformation by inducing cell proliferation
• Platelet-derived growth factor (PDGF) is released from platelets during coagulation, induces proliferation of cells to participate in wound healing.
• SIS oncogene is structurally similar to PDGF beta chain.
• Wnt/Beta-catenin signalling important in embryonic development and adult tissue homeostasis. Inappropriate activation can lead to cancer (e.g. breast cancer)

Question 5

Growth factor receptor class of oncogenes

Answer 5

• Growth factor receptors are altered in many cancers (transduce signals for cell growth and proliferation)
• e.g. Epidermal GFR in non-small cell lung cancer. Activating mutations in tyrosine kinase domain lead to increased kinase activity. Or mutations in ATP binding pocket, causing reduced affinity. Increases their sensitivity to EGFR-TKIs which compete with ATP for catalytic site. TKI therapy leads to apoptotic signalling.
• RET encodes a receptor tyrosine kinase. Activating variants cause MEN2 (multiple endocrine neoplasia 2). Risk of medullary carcinoma.

Question 6

Signal transducer class of oncogene

Answer 6

• Includes PI3Ks (phosphatidylinositol-3-kinases). Class 1 PI3ks catalyse the phosphorylation of inositol containing lipids (phosphatidylinositols).
• Transmit signals from receptor tyrosine kinases and g-protein coupled receptors.
• pi3ks phosphorylate PIP2 into PIP3 (then stimulates downstream pathways via AKT)
• PTEN dephosphorylates PIP3 to PIP2
• PI3K signalling is often deregulated in cancer.
• e.g. mutations that constitutively activate AKT.
• 13% tumours have PIK3CA mutations

Question 7

Inhibitors of apoptosis class of oncogenes

Answer 7

• E.g. BCL2.
• BCL2 encodes a protein that localises to mitochondria and inhibits apoptosis.
• Overexpression of BCL2 follicular lymphomas.
• t(14;18) commonly occurs in follicular lymphomas. Places BCL2 next to immunoglobulin heavy chain locus. Leads to very high levels of BCL2 transcription (less likely to undergo apoptosis).

Question 8

Two main pathways that lead to apoptosis

Answer 8

• Stress

- Death receptor

Question 9

Stress pathway

Answer 9

-inhibition of BCL2 leads to apoptosis, via caspase 9

Question 10

Death receptor pathway

Answer 10

-Binding of a Fas ligand, TRAIL and Tumour necrosis factor alpha to receptors on cell surface. Activates caspase8 causing cell death.

Question 11

Transcription factor class of oncogenes

Answer 11

e. g. EWS/Fli1
- Ewing sarcoma (tumours of bones and soft tissue) due to translocation t(11;22)(q24;q12)
- 3’ end of Fli1 (transcription factor) to 5’ end of EWS gene. (80% of cases)
- Chimeric oncoprotein acts as an aberrant TF with strong transforming capabilities.

Question 12

Example of point mutation activating oncogene

Answer 12

• BRAF p.Val600Glu. Found in malignant melanomas and metastatic colorectal cancer
• Variant produces a hyper-activated protein (normal amounts produced)

Question 13

Example of activating a oncogene by amplification

Answer 13

• e.g. HER2 (human epidermal growth factor 2)
• Found on the surface of breast cells. In cancer there are often multiple copies (normal structurally). Leads to over-production of protein. Identified by FISH or array CGH

Question 14

Example of activating a oncogene by translocation

Answer 14

• Novel chimeric genes, e.g. BCR-ABL
• Philadelphia chromosome. In 90% of patients with chronic myeloid leukaemia (CML).
• Balanced translocation t(9;22)(q34;q11)

Question 15

Example of activating a oncogene by insertional mutagenesis

Answer 15

• e.g. Hepatitis B in hepatocellular carcinoma

- Viral oncogenes insert near cellular genes such as MYC. Causes aberrant activation, and thus unchecked proliferation.