Abstract 6337: A novel PMS2 mutant Lynch syndrome mouse model for cancer prevention studies

Abstract Mono-allelic germline pathogenic variants (GPVs) in MMR genes (MLH1, MSH2, PMS2, and MSH6) predispose individuals to hereditary non-polyposis colorectal cancer (HNPCC), better known now as Lynch syndrome (LS). Bi-allelic GPVs in MMR genes lead to a severe phenotype, constitutional MMR deficiency (CMMRD), that is characterized by early onset of leukemia/lymphoma, colorectal/gastrointestinal tumors, brain tumors, and sarcomas. MMR deficient mouse models have provided many mechanistic and translational insights. Pms2-null (Pms2ko/ko) mice were found to be viable but showed an increase in microsatellite instability and developed lymphomas and sarcomas. One of the most frequently occurring human mutations in PMS2 is a founder mutation NM_000535.5:c.2002A>G (p.I668V), observed in the Canadian Inuit population (1 in 16 Inuits are carriers). This mutation acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). A mouse model with an equivalent germline mutation (Pms2c.1993A>G) results in a splicing defect like that observed in humans and exhibits a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant (Apctm1Rak ) background. We are now further characterizing this model for intestinal tumor initiation and progression using time course experiments and comparing tumor development by histopathological examination with the Pms2ko/ko model. Moreover, we are also examining this model to identify neoantigens, that may lead to development of a new vaccine for PMS2 mutation carriers.This mouse model can be a valuable tool to test the efficacy of new strategies for cancer prevention in PMS2 mutation carriers. We have developed a luciferase based splicing reporter assay in HEK293 cells that can be used to screen splicing modulators to suppress aberrant splicing of this splice site mutation. The efficacy of these modulators to suppress aberrant splicing in the small intestine of mice can be further tested using this mouse model. Citation Format: Kajal Biswas, Yurong Song, Vaishnavi Peddibhotla, Brandon Somerville, Mary Albaugh, Dillon Dierman, Rameesha Mustafa, Altaf Mohammed, Shyam K. Sharan, Robert H. Shoemaker. A novel PMS2 mutant Lynch syndrome mouse model for cancer prevention studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6337.