Germline diagnosis of Lynch syndrome in mismatch repair-deficient colorectal cancer: A case series from Bach Mai Hospital

Abstract

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) but is frequently missed by family-history-based criteria. We report an immunohistochemistry (IHC)-triggered, next-generation sequencing (NGS)-confirmed diagnostic pathway for LS in patients with mismatch repair-deficient (dMMR) CRC at Bach Mai Hospital in 2025. Three BRAF V600E wild-type dMMR CRC patients underwent germline NGS, and a molecular diagnosis of Lynch syndrome was established in two. Case L1, a 41-year-old man with a poorly differentiated descending-colon adenocarcinoma, carried a pathogenic MLH1 frameshift variant (c.793del, p.Arg265ValfsTer3). Case L2, a 33-year-old man with synchronous transverse-colon and splenic-flexure tumours, carried a likely pathogenic MSH2 missense variant (c.1865C>G, p.Pro622Arg); a preoperative biopsy showed proficient MMR whereas the resection showed MSH2/MSH6 loss, illustrating clonal MMR heterogeneity. The third patient (Case N1) had MLH1/PMS2 loss but no detectable germline variant, consistent with a possible Lynch-like syndrome pending methylation testing. In each patient, the IHC loss pattern correctly directed germline testing. These cases support germline testing of all dMMR colorectal cancers independent of family history and highlight the genetic-counselling and cascade-testing implications for probands and at-risk relatives.