Oncogenes Flashcards
What is an oncogene?
A gene normally involved with controlling cellular proliferation.
When altered/over-activated, they help transform normal cells > tumour cells by promoting uncontrolled cell growth and/or inhibiting apoptosis (GAIN OF FUNCTION)
What are the five main pathways for activation of oncogenes?
- Point mutations
- Gene amplification
- Chromosomal translocations
- Local DNA rearrangements
- Insertional mutagenesis
Can you provide some info on point mutations in the activation of oncogenes?
Lead to hyper-activated protein usually produced in normal amounts.
Can occur spontaneously or as a result of environmental influences (e.g. UV or carcinogens).
Example 1: RAS family (HRAS/KRAS/NRAS)
Mutations in these lead to activation of downstream GTP signalling by blocking integral GTPase activity (= molecular switch) - mainly colorectal cancer (plus lung, breast, bladder)
Example 2: BRAF
Val600Glu activating mutation found in malignant melanomas/colorectal
Can you provide some info on gene amplification in the activation of oncogenes?
Multiple copies of growth factor or transcription factor receptors on wild type cell surface, which leads to over-production of coding protein
HER2 - breast cancer cells often have multiple copies of HER2 causing over-production of the protein. Each copy is structurally wild-type and the oncogenic effect comes from the increased copy number (detected by FISH/array/NGS).
Can you provide some info on chromosomal translocation in the activation of oncogenes?
Two types:
- Translocation to create novel chimeric gene (e.g. BCR-ABL) - Philadelphia chr (90% of CML) arising from balanced trans t(9;22)(q34;q11) creating a fusion oncogene (BCR-ABL1)
- Translocation into a transcriptionally active region - there are over 700 known recurrent trans in cancer involving over 400 gene pairs - thought to be linked to DNA breakage/fragile sites. One characteristic example = Burkitt lymphoma - t(8;14)(q24;q32) seen in 75% of patients - involves the MYC gene.
Can you provide some info on local DNA rearrangements in the activation of oncogenes?
Insertion/deletion/inversion of intervening region between each contributing gene can result in fusion genes = abnormal hyperactive proteins
Can you provide some info on insertional mutagenesis in the activation of oncogenes?
Viral oncogenes insert near cellular genes such as MYC and aberrantly activate it to initiate unchecked cellular proliferation.
E.g. Hep B in hepatocellular carcinoma
What are the five broad classes of oncogenes?
- Secreted growth factors
- Growth factor receptors
- Signal transducers
- Inhibitors of apoptosis
- Transcription factors
Provide some info on secreted growth factor oncogenes
Constitutive activation of a growth factor gene can contribute to malignant transformation by inducing cell proliferation.
Example: Platelet-derived growth factor (PDGF) is released from platelets during coagulation and wound healing and can induce proliferation of various adjacent cell types (SIS oncogene = mutated version of PDGF-Beta chain)
Provide some info on growth factor receptor oncogenes
Growth factor receptors are altered in many cancers where they transduce signals for cell growth and proliferation
Example: activating mutations in EGFR in NSCLC cause increased kinase activity
Example: activating mutation in RET oncogene cause multiple endocrine neoplasia type 2 (MEN2)
Provide some info on signal transducer oncogenes
Mutations/truncations can impact ligand-independent signalling, leading to the upregulation of various oncogenic processes (incl. chronic cell cycle proliferation).
Example: PIK3CA activating mutations
Provide some info on apoptosis inhibitor oncogenes
Overexpression of inhibitors of apoptosis has been repeatedly reported in various cancers and is associated with tumourigenesis, treatment resistance and poor prognosis.
Example: Overexpression of BCL2 protein (e.g. via t(8;14) trans) is involved in the initiation of follicular lymphomas - thought to impact stress pathway of apoptosis
Provide some info on transcription factor oncogenes
Translocations resulting in a fusion protein and producing transcription factors are a well-established malignancy (leukaemic or solid tumour) disease driver.
Example: t(11;22) in Ewings sarcoma results in novel chimeric oncoprotein EWS/Fli1, acts as an aberrant transcription factor with strong transforming capabilities.
