DNA Mismatch Repair and Lynch Syndrome

Mismatch Repair Mechanism and MSI-High Phenotype

DNA polymerase proofreading and mismatch repair together keep replication errors low. MutSα or MutSβ recognises selected mismatches and insertion/deletion loops, while MutLα helps coordinate strand incision, excision and resynthesis. Exact error-rate reductions vary by system and should not be presented as one fixed number.

When both functional copies of an MMR gene are lost or MLH1 is epigenetically silenced, insertion/deletion errors can accumulate at microsatellites. MSI can be assessed with validated PCR or sequencing approaches, while dMMR can be assessed through protein-expression patterns and other methods. Coding frameshifts can generate neoantigens, but immune recognition and treatment response still depend on antigen presentation and the wider tumour environment.

Lynch Syndrome: Clinical Genetics and Cancer Spectrum

Lynch syndrome follows autosomal-dominant inheritance, but cancer risk varies substantially by gene, variant, sex, age and family history. The NCI PDQ describes colorectal, endometrial and other associated cancers and gives dated, gene-specific evidence rather than one universal lifetime-risk range.

Universal tumour screening with MMR immunohistochemistry, MSI or validated sequencing is widely recommended for newly diagnosed colorectal cancers and is used in endometrial-cancer pathways. An abnormal tumour screen is not germline confirmation. Genetics-led evaluation determines whether germline testing and cascade testing are appropriate, and surveillance schedules must come from current specialist guidance rather than this page.

MLH1 Epigenetic Silencing in Sporadic MSI-High Colorectal Cancer

Many colorectal tumours with MLH1/PMS2 loss are sporadic and show MLH1 promoter hypermethylation. BRAF V600E is associated with the sporadic methylated pathway in colorectal cancer and can help refine the probability of Lynch syndrome. Neither BRAF status nor methylation should be converted into an exception-free inherited-risk rule without the full algorithm and clinical context.

Reflex pathways can include BRAF testing and/or MLH1 methylation analysis after MLH1/PMS2 loss. The appropriate route differs by tumour type and local protocol, and constitutional MLH1 epimutation or other uncommon explanations may require specialist consideration. Germline testing decisions should therefore follow the pathology pattern, personal and family history and current genetics guidance.

Pembrolizumab in MSI-High Cancer: Clinical Evidence

Checkpoint-inhibitor evidence for MSI-high/dMMR tumours is indication-, age-, prior-treatment-, test- and product-specific. The first tumour-agnostic approval was historically important, but its exact population and conditions should be read from current labelling rather than shortened to 'any MSI-high tumour'.

In unresectable or metastatic MSI-high/dMMR colorectal cancer, KEYNOTE-177 supported a first-line pembrolizumab approval described by the FDA source below. Other checkpoint regimens have separate evidence and labels. An MSI-high or dMMR result supports an oncology discussion; it does not guarantee response or replace assessment of disease setting and test validity.

Key Takeaways

• ·MMR corrects selected replication mismatches; loss of function can generate MSI, but MSI and dMMR are measured with different assays.
• ·Lynch syndrome requires an inherited-risk interpretation of a pathogenic germline finding; tumour dMMR or MSI-high is a screening clue, not the diagnosis.
• ·MLH1 methylation and BRAF V600E can support a sporadic colorectal pathway, but rare exceptions and tumour-type differences prevent an absolute rule.
• ·Checkpoint evidence is product-, disease-, prior-treatment- and test-specific, and no biomarker guarantees response.
• ·Universal tumour screening is widely used for colorectal cancer, while germline confirmation, family testing and surveillance require genetics-led care.