GeneticsTier 1Medical Sciences concept

Knudson two-hit hypothesis (tumour suppressor gene inactivation)

Core concept

Tumour suppressor genes require both alleles inactivated ("two hits") before cancer develops -- unlike oncogenes, where one activating mutation can be sufficient
Sporadic cancer: both hits are somatic, occurring independently in the same cell -- rare, requires two chance mutations in one cell lineage
Hereditary cancer syndrome: first hit is inherited (germline), present in every cell from birth -- only a single additional somatic hit is needed in any one cell -> much earlier onset, often bilateral/multifocal

Retinoblastoma (RB1 gene) is the original/classic example: hereditary form presents younger, often bilateral; sporadic form presents later, unilateral
Second hit mechanisms include point mutation, deletion, or loss of heterozygosity (LOH) -- LOH (losing the remaining normal allele) is a common exam-tested mechanism
Applies broadly beyond retinoblastoma: BRCA1/2 (breast/ovarian cancer), APC (FAP), TP53 (Li-Fraumeni), VHL, NF1/NF2, MLH1/MSH2 (Lynch syndrome) -- all tumour suppressors following two-hit logic

Trap: a family history of early-onset or bilateral/multifocal cancer strongly suggests a hereditary tumour suppressor syndrome (first hit already present in every cell) -- prompts germline testing, not just reassurance about "bad luck"
Genetic counselling implication: a carrier of a germline tumour suppressor mutation has markedly increased lifetime cancer risk because only one further somatic event is needed, not two
Screening/surveillance programmes (e.g. RB1 carrier eye screening, BRCA surveillance) exist specifically because the "second hit" risk is high and ongoing throughout life in every susceptible tissue

Directly contrasts with oncogene activation (e.g. RAS, MYC) -- a single activating mutation in one allele is sufficient, no "two-hit" requirement
Loss of heterozygosity is the same mechanism tested in somatic vs germline mutation distinction -- LOH converts a heterozygous germline carrier into a fully-inactivated somatic cell
Underlies the rationale for prophylactic surgery (e.g. mastectomy/oophorectomy in BRCA carriers) -- removing tissue at risk of acquiring the second hit

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