# Traditional and New Views on MSI-H/dMMR Endometrial Cancer

## TL;DR

This paper reviews the role of traditional and nontraditional MMR genes in dMMR endometrial cancer and explores treatment strategies to improve precision diagnosis and therapy.

## Contribution

The paper highlights the overlooked impact of somatic mutations in traditional MMR genes and the role of nontraditional MMR genes in dMMR endometrial cancer heterogeneity.

## Key findings

- dMMR endometrial cancer includes subtypes with distinct immune microenvironments, such as LS-associated, sporadic, and Lynch-like EC.
- Over 50% of MSI patients do not respond to immune checkpoint inhibitors, possibly due to nontraditional MMR gene abnormalities.
- The paper emphasizes the need to understand dMMR EC heterogeneity for better precision diagnosis and treatment.

## Abstract

MSI-H/dMMR endometrial cancer (EC) is closely linked to the mismatch repair (MMR) pathway, and its pathogenesis is associated with microsatellite instability (MSI) caused by abnormalities in the core genes of the conventional MMR system. This cancer exhibits a distinct immune microenvironment, which makes it suitable for treatment with immune checkpoint inhibitors (ICIs). This cancer type demonstrates heterogeneity, encompassing Lynch syndrome (LS)-associated EC (characterized by germline mutations), sporadic EC (attributed to MLH1 promoter hypermethylation), and Lynch-like EC (driven by somatic mutations). Research indicates that these three dMMR EC subtypes possess different immune microenvironments, which may influence the therapeutic efficacy of ICIs. However, the impact of somatic mutations in traditional MMR genes on EC has often been overlooked. Furthermore, over 50% of patients with MSI exhibit no response to ICIs, potentially due to abnormalities in nontraditional MMR genes. This review discusses the role of traditional and nontraditional MMR genes in dMMR EC and related treatment strategies, highlights key issues in the current diagnosis and treatment of dMMR EC, and aims to enhance understanding of its heterogeneity and advance precision diagnosis and treatment.