Synopsis
Identify inherited colorectal cancer risk, interpret tumour and germline testing in sequence, and connect patients and relatives to gene-specific surveillance, prevention and surgical planning.
- Lynch syndrome is usually autosomal dominant and caused by a germline pathogenic variant affecting MLH1, MSH2, MSH6, PMS2 or EPCAM-mediated MSH2 silencing; it produces cancer predisposition without carpeting polyposis.
- Familial adenomatous polyposis is an autosomal dominant APC-associated syndrome with tens to thousands of adenomas and near-inevitable colorectal cancer without effective surveillance and prophylactic surgery.
- MUTYH-associated polyposis is autosomal recessive; biallelic carriers have important colorectal risk, while risk and management for a single variant differ and require contextual genetics advice.
- NICE recommends MMR immunohistochemistry or microsatellite-instability testing for every newly diagnosed colorectal cancer, followed by the appropriate tumour and germline sequence without delaying cancer treatment.
- Loss of MLH1 requires BRAF V600E and MLH1 promoter-hypermethylation assessment to distinguish many sporadic tumours before constitutional testing; other isolated MMR losses direct germline evaluation.
- BSG surveillance for Lynch syndrome is two-yearly colonoscopy from age 25 for MLH1 or MSH2 and from age 35 for MSH6 or PMS2, generally to age 75, unless individual factors alter it.
- For a confirmed APC-associated FAP carrier, colorectal surveillance normally starts at age 12 to 14 and repeats every one to three years according to phenotype while prophylactic surgery is planned.
- Cascade testing begins with the familial pathogenic variant, allowing relatives who carry it to enter surveillance and those who do not to avoid unnecessary syndrome-level procedures.
Key red flags
Hundreds to thousands of colorectal adenomas developing from adolescence, often with an APC pathogenic variant and extracolonic features, require registry surveillance and planned prophylactic colorectal surgery.
Anaemia, weight loss, bleeding, progressive bowel change or obstruction in a carrier is investigated as possible cancer immediately; scheduled surveillance must not become a reason to wait.
Investigation priorities
Estimate inherited probability and identify the most informative affected relative and syndrome-specific cancers or polyps.
Management branches
A person is newly diagnosed with colorectal cancer at any age.
- Order or verify four-protein MMR immunohistochemistry or MSI testing and record responsibility for acting on the result without delaying staging or cancer treatment.
- For abnormal MLH1, follow the NICE BRAF V600E then MLH1 promoter-methylation sequence; for other abnormal loss patterns, progress to appropriately counselled germline testing.
- Discuss tumour findings in colorectal MDT because mismatch-repair status can affect prognosis and systemic-treatment choices as well as inherited-risk assessment.
- Refer a likely inherited or unexplained deficient-MMR result to genetics, communicate implications carefully and ensure relatives are not tested against an unconfirmed assumption.
Key medicines
Aspirin chemoprevention in Lynch syndromeNICE advises considering daily aspirin for more than two years; select the actual dose through shared specialist decision using current guidance and individual risk.Assess ulcer or bleeding history, anaemia, anticoagulants, allergy, asthma, kidney disease and H pylori context. Optimal dose is uncertain; do not extrapolate one trial dose as mandatory for everyone.
Bowel-cleansing preparationUse a split-dose local regimen timed for high-quality surveillance, modified for age, renal or cardiac disease, constipation burden and the selected endoscopy list.Check obstruction, swallowing, dehydration, electrolytes and interacting medicines. Repeated poor preparation in a high-risk carrier needs pathway redesign rather than acceptance of a compromised examination.