Colorectal Cancer and Lynch Syndrome
On this page
Direct answer
Lynch syndrome is an autosomal dominant hereditary colorectal cancer predisposition caused by germline mutations in DNA mismatch repair genes, most often MLH1 and MSH2. It accounts for a small minority of colorectal cancers but carries a high lifetime risk of colorectal and endometrial cancer. Tumour testing for microsatellite instability and early colonoscopy surveillance are the basis of its management.
What you must remember
- Mismatch repair genes: MLH1, MSH2, MSH6, PMS2 and EPCAM deletions; loss of protein or microsatellite instability (MSI-high) on tumour testing points to Lynch syndrome.
- Amsterdam II criteria: Three relatives with Lynch-associated cancer, one a first-degree relative of the other two, two successive generations, one diagnosed before 50, and familial adenomatous polyposis excluded.
- Revised Bethesda guidelines: Tumour testing for MSI in colorectal cancer patients, for example those diagnosed before 50, to decide who needs germline testing.
- Tumour features: Right-sided, mucinous or signet-ring histology, poor differentiation, tumour-infiltrating lymphocytes and a Crohn-like lymphocytic reaction.
- Sporadic MSI-high: BRAF V600E mutation with MLH1 promoter hypermethylation points to a sporadic cancer, not Lynch syndrome.
- Surveillance: Colonoscopy every one to two years from about age 20 to 25, with gynaecological screening discussed; MSI-high metastatic colorectal cancer responds to immune checkpoint inhibitors.
A pathway from family history to diagnosis
A 42-year-old man has right-sided colon cancer. His mother had endometrial cancer at 46 and his sister had colon cancer at 38.
- Apply Amsterdam II: The patient, his mother and his sister make three relatives with Lynch-associated cancer, he is a first-degree relative of the other two, two generations are involved and one case is before 50, so the criteria are met once polyposis is excluded.
- Apply revised Bethesda: The tumour-testing criterion is also met because the patient's cancer was diagnosed before 50.
- Test the tumour: Immunohistochemistry shows loss of MSH2 and MSH6 with MSI-high status, which makes germline testing appropriate.
- Confirm the germline mutation: Germline testing for MSH2, the most likely gene, is the next step, and the result allows cascade testing of relatives.
- Start surveillance in relatives: Siblings and children with a confirmed mutation begin colonoscopy at the young age recommended for Lynch syndrome. The mother is assessed for endometrial surveillance and risk-reducing options.
- Exclude sporadic disease: If the tumour had instead carried a BRAF V600E mutation with MLH1 promoter hypermethylation, the case would be sporadic and would not justify a germline diagnosis.
Each branch of this pathway is a common question, so the sequence of criteria, tumour testing and germline confirmation is worth memorising.
Where the exam tries to catch you
Four confusions recur on this topic.
- Trap: mixing Lynch syndrome with familial adenomatous polyposis Correct: Lynch syndrome produces few adenomas, typically on the right side, whereas familial adenomatous polyposis produces hundreds of polyps throughout the colon.
- Trap: confusing the Amsterdam and Bethesda criteria Correct: Amsterdam is a family-history clinical rule, while Bethesda guides tumour testing.
- Trap: assuming the cancer risk is uniform across the syndrome Correct: MSH6 and PMS2 mutations generally carry a lower cancer risk and later onset than MLH1 or MSH2.
- Trap: diagnosing Lynch syndrome from MSI-high status alone Correct: check BRAF and methylation status first, since a sporadic MSI-high tumour is a common distractor.
Frequently asked questions
Which genes are most commonly mutated in Lynch syndrome?
MLH1 and MSH2 are the most commonly mutated genes in Lynch syndrome, followed by MSH6 and PMS2, all involved in DNA mismatch repair. Tumour testing for microsatellite instability or loss of mismatch repair protein screens for these defects.
What are the Amsterdam II criteria for Lynch syndrome?
The Amsterdam II criteria require three relatives with Lynch-associated cancers, one a first-degree relative of the other two, involvement of at least two successive generations, one case diagnosed before age 50, and exclusion of familial adenomatous polyposis. Tumours should be pathologically verified.
What distinguishes sporadic MSI-high colorectal cancer from Lynch syndrome?
BRAF V600E mutation together with MLH1 promoter hypermethylation points to sporadic MSI-high colorectal cancer rather than Lynch syndrome. Lynch syndrome is more likely when MLH1 loss occurs without promoter methylation, or when a germline mutation is confirmed.
At what age should colonoscopy surveillance start in Lynch syndrome?
Colonoscopy surveillance in Lynch syndrome generally starts at about age 20 to 25 and repeats every one to two years, which is earlier than average-risk screening. The start age and interval depend on the specific gene and family history.
Is aspirin used for chemoprevention in Lynch syndrome?
Aspirin is discussed as chemoprevention in Lynch syndrome because it reduces colorectal cancer risk in some studies, but it does not replace colonoscopy. Current guidance on dose and timing should be checked before prescribing.