A EPCAM Pathogenic Variant in Familial Lynch Syndrome-Associated Colon Cancer: Insights into Genetic Basis and Tumor Microenvironment Characteristics.

Lynch syndrome (LS) is an inherited condition caused by germline mutations in genes involved in DNA mismatch repair (MMR), which could increase the risk of developing colorectal cancer and other types of cancers. Current understanding of MMR gene mutations cannot fully account for the genetic predisposition to LS-associated colon cancer. This study uncovered a novel germline mutation, EPCAM c.661 A > G, in members of a three-generation family using next-generation sequencing technique, which was related to a vertically transmitted risk for LS-associated colon cancer. Genetically, EPCAM c.661 A > G was proposed to modulate the transcriptional activity of MSH2 through the DNA methylation alteration, as well as influence the stability of EpCAM protein. Through spatial transcriptomic analysis, we discovered a "cold" tumor microenvironment feature and distinct cellular interactions among epithelial cell subpopulations. In conclusion, these findings highlight the importance of identifying and characterizing novel pathogenic mutations of MMR genes to better understand the genetic basis of LS and its association with colon cancer.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-024-00202-9.