Hereditary cancer susceptibility genes (BRCA1/2, TP53, PALB2, RET, VHL, MEN1)
Core concept
- ~5-10% of cancers are germline-driven; almost all are autosomal dominant with a two-hit somatic second event
- Three mechanistic families - the family predicts the biology and the drug
- DNA repair / caretaker genes - BRCA1, BRCA2, PALB2, ATM, CHEK2, mismatch repair
- Loss -> genomic instability; synthetic lethality with PARP inhibition (BRCA/PALB2) or neoantigen load -> checkpoint inhibitor response (MMR)
- Classical tumour suppressors / gatekeepers - TP53, RB1, APC, PTEN, VHL, MEN1, NF1/NF2, STK11, CDH1
- Loss of function, both alleles needed
- Proto-oncogenes - RET, MET
- Gain of function, activating, single allele sufficient -> the only one where a germline mutation is activating
- DNA repair / caretaker genes - BRCA1, BRCA2, PALB2, ATM, CHEK2, mismatch repair
- Red flags for a germline cause: young age, bilateral or multifocal disease, multiple primaries, rare histology or rare site, a syndromic constellation, Ashkenazi ancestry, strong family history
- A negative family history does not exclude it - de novo TP53 is ~7-20% of Li-Fraumeni
3 more sections, plus exam facts
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