Mismatch Repair Deficiency in Upper Gastrointestinal and Pancreaticobiliary Cancers: Integrating Multimodal Molecular Data in Clinical Practice.

MLH1

Mismatch repair deficiency of epigenetic origin (MLH1 promoter methylation), somatic or germline

The authors reviewed 91 mismatch repair-deficient upper gastrointestinal and pancreaticobiliary cancers from 90 patients at a tertiary academic centre, assessing immunohistochemistry patterns and the use of ancillary molecular tests. The most common primary sites were stomach (44%), oesophagus (16%) and small bowel (12%). Paired MLH1-PMS2 loss predominated (78%), followed by unusual loss patterns (12%) and paired MSH2-MSH6 loss (10%); immunohistochemistry and microsatellite instability testing were discordant in 16% of tested cases (3 of 19). MLH1 promoter methylation was present in 80% of tested tumours with MLH1-PMS2 loss (37 of 46). Lynch syndrome was identified in 17% of patients who underwent genetic testing (6 of 36), and somatic mismatch repair gene variants were found in 43% of sequenced tumours (9 of 21).

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

The figure to retain for the cancer genetics clinic is the 17% rate of Lynch syndrome among tested patients: outside colorectal and endometrial cancer, mismatch repair deficiency in a gastric, oesophageal or pancreaticobiliary tumour deserves the same referral reflex. The 16% discordance between immunohistochemistry and microsatellite instability testing, even across only 19 tumours, argues against relying on a single test before concluding. The series remains single-centre and heavily affected by ascertainment — only 36 of 90 patients underwent germline testing and 21 tumour sequencing — so the 17% figure likely overestimates what systematic testing would show.

Analysis by Dr Thibaut Benquey