Q2 LONG ANSWER 10M ★ High-yield

Describe the molecular basis of cancer. Discuss oncogenes, tumour suppressor genes and DNA repair genes with examples.

Pathology · 2nd Professional — Para-Clinical

The Central Principle

Cancer is a genetic disease of somatic cells: it arises from the accumulation of mutations in genes controlling growth, differentiation, death and DNA repair, so that a single clone escapes normal restraint.

Carcinogenesis is a multistep process — several mutations are needed, which is why cancer incidence rises so steeply with age
Tumours are monoclonal — derived from a single transformed cell, demonstrated by X-linked enzyme and immunoglobulin gene rearrangement studies

The Four Classes of Gene Involved

Class	Normal role	Effect of mutation	Inheritance in the cell
Proto-oncogenes	Promote growth	Gain of function — becomes an oncogene	Dominant — one allele is enough
Tumour suppressor genes	Inhibit growth — the "brakes"	Loss of function	Recessive — both alleles must be lost (knudson two-hit hypothesis)
Genes regulating apoptosis	Trigger or prevent programmed cell death	Either gain (anti-apoptotic) or loss (pro-apoptotic)	Variable
DNA repair genes	Maintain genomic integrity — "caretakers"	Loss leads to a mutator phenotype; mutations accumulate everywhere	Recessive

Important Oncogenes

Oncogene	Mechanism of activation	Tumour
RAS	Point mutation locking it in the GTP-bound active state	The commonest oncogene in human cancer — about 30%; pancreas, colon, lung, thyroid
MYC	Translocation t(8;14) placing it under the immunoglobulin heavy chain promoter	Burkitt lymphoma
N-MYC	Amplification	Neuroblastoma — amplification indicates poor prognosis
HER2/neu (ERBB2)	Amplification	Breast carcinoma — the target of trastuzumab
ABL	Translocation t(9;22) — the philadelphia chromosome, forming BCR-ABL	Chronic myeloid leukaemia — the target of imatinib
Cyclin D1 (CCND1)	Translocation t(11;14); amplification	Mantle cell lymphoma; breast
EGFR	Mutation, amplification	Lung adenocarcinoma — the target of gefitinib
RET	Point mutation	Men 2A and 2B; medullary thyroid carcinoma
Bcl-2	Translocation t(14;18)	Follicular lymphoma — cells accumulate because they do not die

Important Tumour Suppressor Genes

Gene	Locus	Function	Associated cancers
RB	13q14	The "governor" of the cell cycle — hypophosphorylated RB blocks the G1→S transition	Retinoblastoma, osteosarcoma
P53 (TP53)	17p13	"guardian OF the genome" — arrests the cycle for repair, or triggers apoptosis if repair fails	Mutated in over 50% of all human cancers; germline mutation causes LI–fraumeni syndrome
APC	5q21	Regulates beta-catenin in the WNT pathway	Familial adenomatous polyposis; most sporadic colorectal cancer
BRCA1 and BRCA2	17q and 13q	DNA double-strand break repair	Familial breast and ovarian carcinoma
NF1, NF2	17q, 22q	RAS GTPase activation; merlin	Neurofibromatosis 1 and 2
VHL	3p	Degrades hypoxia-inducible factor	Renal cell carcinoma, haemangioblastoma, phaeochromocytoma
WT1	11p	Transcription factor	WILMS tumour
PTEN	10q	Inhibits the PI3K/AKT pathway	Endometrial, breast, prostate

CLINICAL PEARL

Knudson's two-hit hypothesis explains why the same gene gives both familial and sporadic cancer. In the familial form the child inherits one defective allele in every cell and needs only one further mutation — so tumours appear early and are often bilateral or multiple. In the sporadic form both hits must occur in the same somatic cell, which is rare — so the tumour appears late and is solitary. Retinoblastoma is the model.

DNA Repair Genes and the Hallmarks of Cancer

Repair system	Defect causes	Feature
Mismatch repair (MLH1, MSH2)	LYNCH syndrome (hereditary non-polyposis colorectal cancer)	Microsatellite instability
Nucleotide excision repair	Xeroderma pigmentosum	Cannot repair ultraviolet-induced pyrimidine dimers; severe photosensitivity and multiple skin cancers in childhood
Homologous recombination (BRCA, ATM)	Familial breast and ovarian cancer; ataxia telangiectasia	Sensitivity to radiation; exploited by PARP inhibitors

The hallmarks of cancer

Self-sufficiency in growth signals — oncogenes
Insensitivity to growth-inhibitory signals — tumour suppressors
Evasion of apoptosis
Limitless replicative potential — through reactivation of telomerase
Sustained angiogenesis
Invasion and metastasis
Reprogrammed metabolism — the warburg effect, aerobic glycolysis, which is the basis of pet scanning
Evasion of the immune system

Applied Aspects

Targeted therapy follows directly from the molecular lesion — imatinib for BCR-ABL, trastuzumab for HER2, gefitinib for mutated EGFR; each works only in tumours carrying that change, so testing precedes treatment
PARP inhibitors exploit synthetic lethality in BRCA-mutant tumours — blocking the remaining repair pathway kills cells that have already lost the other
Microsatellite instability testing identifies Lynch syndrome and also predicts response to immune checkpoint inhibitors
Genetic counselling and surveillance transform outcomes in familial cancer syndromes — colonoscopy in familial polyposis, risk-reducing surgery in BRCA carriers
Liquid biopsy detects circulating tumour DNA, allowing non-invasive monitoring and early detection of resistance mutations
Epigenetic changes matter as much as mutations — hypermethylation of a tumour suppressor promoter silences it as effectively as deleting it, and is potentially reversible
Chromosomal instability and aneuploidy are near-universal in solid tumours, and follow from loss of the checkpoints described above
Tumour heterogeneity means different regions of one tumour carry different mutations, which is why a single biopsy may mislead and why resistance emerges
Immune checkpoint inhibitors work best in tumours with a high mutational burden, since more mutations mean more neo-antigens for the immune system to recognise

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