MLH1

This study investigated DNA methylation profiles in 259 sporadic colorectal cancers, aiming to identify microsatellite instability (MSI)-associated signatures beyond the CIMP phenotype and MLH1 promoter hypermethylation. Researchers discovered 656 differentially methylated CpG sites linked to MSI, including hypermethylation of LRP6, GSK3B, and CDK12, genes involved in WNT signaling and transcriptional regulation. The study also revealed heterogeneity within MSI CRCs, with co-occurrence of MLH1 and TXNRD1 promoter hypermethylation. Furthermore, anatomical location was found to be a major determinant of the CRC methylome, contributing to improved molecular stratification of the disease.

This large genomic analysis of 2901 endometrial carcinomas refines molecular classification by addressing several clinical questions. The study confirms that all four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) confer an equivalently favorable prognosis, validating dMMR status as a class-level prognostic designation. It demonstrates that the exceptional survival benefit associated with POLE-ultramutated tumors is confined to canonical exonuclease-domain hotspot mutations, excluding variants of uncertain significance. Finally, patients with TP53 mutations and high copy-number instability (CNH) are identified as having the most urgent unmet therapeutic need.

The FIGO staging system for endometrial cancer underwent a significant revision in 2023, incorporating refined anatomical criteria and molecular determinants. This update aims to optimize adjuvant treatment selection by maximizing therapeutic benefits while minimizing harm. Molecular subgroups include POLEmut, p53abn, MMRd, and NSMP. The 2025 ESGO-ESTRO-ESP recommendations further enhance this framework by mandating estrogen receptor (ER) assessment within the NSMP category, identifying early-stage disease with an increased risk of recurrence and mortality.