Adenomas Are Frequent in PMS2 Lynch Syndrome patients but Rarely Mismatch Repair Deficient

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Abstract Background Lynch syndrome (LS) predisposes carriers to the accelerated development of colorectal cancer (CRC). Pathogenic PMS2 variant (PV) carriers are believed to have the lowest CRC risk and develop MMR deficiency (dMMR) at a later stage of CRC progression. In addition, the PMS2 adenoma incidence rate is considered lowest among all MMR PV carriers. However, neither the exact adenoma incidence nor the prevalence of dMMR among PMS2 PV carriers is known. Method We established a cohort of 171 confirmed PMS2 PV carriers in the Netherlands and collected clinical excerpts to establish adenoma incidence. We also collected 123 paraffin blocks from PMS2 PV carriers and investigated PMS2 and MLH1 expression with immunohistochemistry (IHC). Results We collected 123 paraffin blocks containing adenomatous lesions from PMS2 PV carriers removed who underwent surveillance colonoscopy between 2018-2023. Of the 123 IHC-stained lesions 109 were tubular adenomas, 86.2% of which (n=94/109) retained PMS2 protein expression. All specimens showed intact MLH1 staining. Conclusion Adenomas are frequent in PMS2 PV carriers, although the majority of PMS2-associated adenomas retained MMR-proficiency. The result of our study corroborates the late involvement of PMS2 deficiency in the evolution of to PMS2 associated CRC.

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