Unique MLH1 mutations in colonic adenomas in an obligate germline Lynch syndrome carrier.

ABSTRACT

BACKGROUND: An obligate germline Lynch syndrome carrier had four colonic adenomas removed. MATERIALS AND METHODS: The adenomas were evaluated for grade of dysplasia, MLH1, PMS2, MSH2 and MSH6 protein expression, microsatellite instability (MSI), BRAF, methylation status and a next-generation sequencing (NGS) panel of 52 cancer genes. RESULTS: There were four tubular or tubulovillous adenomas from the hepatic flexure, rectosigmoid and rectum; one with low-grade and high-grade dysplasia, one with high-grade dysplasia only and two with low-grade dysplasia. All four adenomas showed retention of MLH1, MHS2 and MSH6 but complete loss of PMS2 in both low-grade and high-grade dysplasia areas.Two of the four adenomas were MSI-high, BRAF V600E wild type and were not MLH1 methylated. NGS identified an MLH1 germline variant NM_000249.3 c.1558+1 G>A, p.(?) in all tissue (adenomas and normal), which likely explains the pathophysiology of Lynch syndrome in this patient. Other variants were also detected in MLH1 and MSH6 in all four adenomas tested; these being reported previously in somatic colorectal cancers. CONCLUSION: We highlight an MLH1 variant in the colonic adenomas in an obligate Lynch syndrome carrier that resulted in PMS2 protein loss in the absence of mutations of the PMS2 gene.