biostudies-literatureBowen MBNCRR NIH HHSFoundation for Women’s CancerNational Cancer InstituteNCI NIH HHSWharton Endowment FundNational Institutes of HealthCancer Prevention and Research Institute of Texase185946https://www.ebi.ac.uk/biostudies/studies/S-EPMC11949016biostudies-literatureUnknown10(6)Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in vivJCI insightMitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.PMC11949016N/AP30CA016672P30CA016086CA016672P30 CA016672P30 CA016086R25CA056452Roberta Detz Endometrial Cancer GrantS10 RR029552R25 CA056452R01 CA216103R01CA216103Chan WKTan LBroaddus RRMoreno DLorenzi PLScoville DMPeralta LZhang QMelendez BSchmandt RKim THLu KBowen MBJeter CDunner KZal MAJeong JWYang RKGokul NWhitley EYates MSKim HECelestino JfalseMitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in viv2025-01-01T00:00:00Z2025 Feb2026-06-02T07:21:21.112Z2025-07-05T03:04:43.754ZS-EPMC119490163996476210.1172/jci.insight.185946