Oncogenes
• Promote cell proliferation and survival when mutated or overexpressed
• Act in a dominant (gain-of-function) manner — single allele mutation sufficient
Examples
• MYC:
o Burkitt lymphoma: t(8;14) → MYC overexpression
o Neuroblastoma: MYCN amplification → poor prognosis
• RAS:
o Point mutations → constitutive activation of MAPK pathway
o Seen in colorectal, pancreatic, lung cancers
• ABL:
o CML: t(9;22) → BCR-ABL fusion gene → constitutive tyrosine kinase activity
Tumour Suppressor Genes (TSGs)
• Normally inhibit cell proliferation, promote apoptosis and DNA repair
• Act in recessive (loss-of-function) manner — both alleles must be inactivated
Examples
• TP53 ("guardian of the genome")
o Induces cell cycle arrest (via p21) or apoptosis after DNA damage
o Mutated in ~50% of all human cancers
o Li-Fraumeni syndrome: germline TP53 mutation → multiple early-onset cancers
• RB (retinoblastoma protein)
o Controls G1 → S checkpoint via E2F
o Retinoblastoma: bilateral cases suggest germline "first hit"
• BRCA1/BRCA2
o DNA repair via homologous recombination
o Hereditary breast, ovarian, prostate, pancreatic cancers
• APC
o Regulates β-catenin (Wnt pathway)
o Mutated in familial adenomatous polyposis (FAP), colon cancer progression
Knudson’s Two-Hit Hypothesis
• For TSGs, both copies (alleles) must be inactivated
• Explains hereditary predisposition (first hit = germline; second hit = somatic)
• Classic example: RB gene in retinoblastoma
p53 — "Guardian of the Genome"
• Monitors DNA integrity → arrests cell cycle or triggers apoptosis
• Mutations lead to:
o Accumulation of damaged DNA
o Resistance to apoptosis
• Loss of p53 function → common in:
o Lung, breast, colorectal, ovarian, and many other cancers
Paraneoplastic Syndromes
Endocrine
• SIADH:
o Small cell lung carcinoma → ectopic ADH
o Leads to euvolaemic hyponatraemia
• Hypercalcaemia:
o Squamous cell lung carcinoma → PTHrP secretion
o Renal cell carcinoma, breast cancer, multiple myeloma (via osteolytic cytokines)
• Cushing’s syndrome:
o Ectopic ACTH production
o Small cell lung carcinoma, neuroendocrine pancreatic tumours
Neurological
• Lambert-Eaton myasthenic syndrome:
o Autoantibodies against presynaptic calcium channels → proximal muscle weakness
o Associated with small cell lung carcinoma
• Paraneoplastic cerebellar degeneration:
o Anti-Yo (breast, gynaecological), Anti-Hu (small cell lung cancer)
Dermatological
• Dermatomyositis/polymyositis:
o Strong associations with ovarian, lung, gastric, pancreatic, colorectal cancers
• Acanthosis nigricans:
o Rapid-onset, widespread
o Gastric adenocarcinoma most classically, also other GI and lung cancers
Hallmarks of Malignancy (Hanahan & Weinberg)
• Sustained proliferative signalling
o Via oncogenes (e.g., RAS, EGFR)
• Evasion of growth suppressors
o Inactivation of TSGs (e.g., TP53, RB)
• Resistance to cell death
o Avoid apoptosis (e.g., BCL-2 overexpression in follicular lymphoma)
• Inducing angiogenesis
o VEGF secretion; hypoxia-inducible factor (HIF-1α)
• Enabling replicative immortality
o Telomerase reactivation → maintains telomere length
• Activating invasion and metastasis
o E-cadherin loss, MMP production
• Deregulating cellular energetics
o Warburg effect: preference for glycolysis even in aerobic conditions
• Avoiding immune destruction
o PD-L1 expression, downregulation of MHC
Extra Revision Pearls
• Warburg effect: many cancers prefer glycolysis → high glucose uptake (basis for PET scans)
• BCL-2 overexpression: follicular lymphoma t(14;18) → apoptosis resistance
• HNPCC (Lynch syndrome): MMR gene mutations (e.g., MLH1, MSH2) → microsatellite instability → colorectal, endometrial, ovarian
• Philadelphia chromosome (t(9;22)): BCR-ABL fusion, hallmark of CML, also seen in some ALL
