Familial cancer syndromes - hereditary non-polyposis colorectal cancer

Description

Lynch syndrome (formerly HNPCC) - autosomal dominant mismatch repair (MMR) deficiency -> markedly inc risk colorectal + endometrial + other cancers
No/few polyps - distinguishes from FAP; cancers arise from few, rapidly-progressing adenomas

Germline mutation in a mismatch repair gene: MLH1, MSH2, MSH6, PMS2 (or EPCAM deletion silencing MSH2)
-> microsatellite instability (MSI-H) -> accelerated accumulation of mutations -> early-onset, multiple cancers
Penetrance and cancer spectrum gene-dependent
- MLH1/MSH2 - highest CRC + endometrial risk, earliest onset
- MSH6/PMS2 - lower penetrance, later onset, endometrial cancer prominent in MSH6

Tumour screening first: all CRC (and endometrial cancer) tested for MMR status - IHC for MLH1/MSH2/MSH6/PMS2 protein loss and/or MSI testing
Loss of MLH1 -> check BRAF V600E / MLH1 promoter hypermethylation to exclude sporadic (methylation-driven) loss before germline testing
Abnormal screen (not explained by methylation) -> germline genetic testing confirms Lynch syndrome, identifies gene
Clinical criteria (Amsterdam/Bethesda) now largely superseded by universal tumour screening
Cascade testing of first-degree relatives once a familial mutation identified

Surveillance (gene- and risk-stratified)

Colonoscopy - from age ~25 (earlier if family history dictates), typically every 1-2 years (interval and start age tailored to gene - MLH1/MSH2 more intensive)
Endometrial/ovarian - discuss risk-reducing hysterectomy +/- BSO after completed family, or annual gynae surveillance if declined
Other surveillance per gene/family history: upper GI endoscopy, urinary tract surveillance in selected high-risk families
Aspirin - reduces CRC incidence with long-term use in Lynch carriers - offer after discussing risks/benefits

If cancer develops

Consider extended/subtotal colectomy over segmental resection - reduces metachronous cancer risk
MMR-deficient tumours - immunotherapy (checkpoint inhibitors) highly effective in metastatic setting

Endometrial cancer - often the sentinel cancer in women, comparable lifetime risk to CRC
Ovarian, gastric, small bowel, urothelial (renal pelvis/ureter), pancreatic, biliary, brain (glioblastoma - Turcot syndrome variant) cancers
Muir-Torre variant - sebaceous neoplasms + keratoacanthomas with Lynch-spectrum cancers

Lifetime CRC risk ~40-70% depending on gene (MLH1/MSH2 highest) without surveillance
Metachronous CRC risk elevated after segmental resection - drives extended resection discussion
Surveillance colonoscopy demonstrably reduces CRC incidence and mortality in Lynch carriers
Family cascade testing is the single highest-yield intervention once a proband is identified

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