Pan-cancer prevalence of microsatellite instability and Lynch syndrome in India.

MLH1, MSH2

Mismatch repair (MMR) deficiency due to germline pathogenic variants, mainly in MLH1 and MSH2, including two recurrent MLH1 variants (c.306G>T and c.156delA, the latter a likely founder variant originating in Gujarat)

Lynch syndrome is underdiagnosed in India, particularly outside colorectal cancer. This study consecutively recruited 519 patients with colorectal or extracolonic cancers from 17 Indian centres between 2019 and 2025, using a tumour-first approach: MSI testing by PCR fragment length analysis in all tumours, MMR immunohistochemistry in extracolonic tumours, BRAF V600E testing in MSI-H colorectal cancers, and germline WES in MSI-H/BRAF wild-type colorectal cancers and MSI-H/dMMR extracolonic tumours. MSI-H/dMMR status was found in 24.9% of tumours (129/519), and 51.2% of these patients (66/129) carried germline pathogenic or likely pathogenic variants consistent with Lynch syndrome, mainly in MLH1 (69.7%) followed by MSH2 (18.2%). Two recurrent MLH1 variants, c.306G>T and c.156delA, together accounted for 36.4% of diagnoses, with haplotype analysis supporting c.156delA as a novel founder variant originating in Gujarat. Concordance between PCR-based MSI testing and MMR immunohistochemistry in extracolonic tumours was 93.8%.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The yield is high: more than one in two MSI-H/dMMR patients carries a germline variant, with a strong concentration on two MLH1 variants, which could justify targeted testing for these variants in the populations concerned. Numbers remain modest for extracolonic tumours, and the authors acknowledge that site-specific yields partly reflect cohort composition. The next challenge is cascade testing, which the abstract recommends without reporting data on it.

Analysis by Dr Thibaut Benquey