Cancer Biology

Question 1

Typically, what types of proteins are proto-oncogenes?

Answer 1

Growth factors (e.g. PDGFRA, PDGFRB, EGF, VEGF)
Growth factor receptors (e.g. EGFR, ERBB2, RET, VEGFR, KIT, NTRK1/2/3, ALK, ROS1)
Intracellular signal transducers (e.g. KRAS, NRAS, HRAS, BRAF, PIK3CA)
Transcription factors (e.g. FOS, JUN, MYC, GLI, MYB)

MicroRNAs may also function as oncogenes

Question 2

What are the main mechanisms of oncogenic activation?

Answer 2

Amplification
Activating point mutations/indels
Exon skipping (e.g. MET exon 14)
Chromosomal rearrangements (e.g.. oncogenic fusions)
Enhancer capture (e.g. a rearrangement bringing a gene under the influence of a novel enhancer)

Question 3

Defective cell cycle checkpoint function can contribute to tumourigenesis. What are the three main cell cycle checkpoints?

Answer 3

G1 checkpoint: between G1 and S, ensures that no damaged DNA gets replicated in S phase. Cell cycle is arrested is damage is detected to allow for repair / move into G0 phase.

G2 checkpoint: during G2; ensures correct completion of DNA replication prior to mitosis; cell cycle arrest induced if damaged or unreplicated DNA is detected, until repaired. ATM/ATR (damage sensors) are activated resulting in the inhibition of relevant cdks + prevention of mitosis.

M checkpoint: during M phase; also known as spindle assembly checkpoint; ensures correct alignment of chromosomes on the metaphase plate and that all sister chromatids are correctly attached to the spindles

Question 4

Growth factors/mitogens regulate the cell cycle. What are the three main ways that growth signalling can be dysregulated in cancer cells?

Answer 4

Autocrine stimulation: tumour cells inappropriately secreting growth factors to stimulate self-growth

Constitutive activation: tumour cells harbouring mutations in growth factor receptor genes (e.g. EGFR) or downstream signalling proteins that cause constitutive activation without require stimulation

Overexpression: tumour cells upregulating/ overexpressing growth factor receptors leading to increased signalling (e.g. HER2 overexpression in breast cancer)

Question 5

What are the main types of tumour suppressor genes?

Answer 5

Caretaker genes: involved in the maintenance of genome stability and include genes implicated in DNA repair (e.g. BRCA1, BRCA2, ATM)

Gatekeeper genes: involved in tumour suppression by inhibiting growth or by promoting cell death (e.g. TP53, APC, NF1)

Landscaper genes: when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation (e.g. PTEN, SMAD4)