Principles of Cancer Biology and Genetics

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