Abstract 7496: Evolutionary trajectories inferred by selective epistasis and phylogenetic analysis reveal the malignant progression of intraductal papillary mucinous neoplasms to pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death, with high mortality rates attributable to late detection when metastases have already occurred. Early-stage PDAC is challenging to detect due to its frequently asymptomatic nature, lack of biomarker sensitivity, and inaccessible anatomical location. Pre-malignant intraductal papillary mucinous neoplasms (IPMNs) are detectable through imaging and can progress to malignant PDAC, offering a unique opportunity for early interventions such as prophylactic resection. However, identification of IPMNs that will become malignant is challenging, and pancreatic resection comes with significant morbidities. Thus, characterizing the evolutionary trajectories by which IPMNs progress to PDAC could both guide surgical decision-making and reveal targetable mechanisms to prevent malignant development. Here, we quantify the evolutionary selection for mutations that lead to IPMNs and compare that result to the selection of known drivers of PDAC. We infer a protective effect of KLF4 mutation in IPMNs on subsequent progression to PDAC that arises due to antagonistic selective epistasis with KRAS and other high-impact contributors to PDAC. We then investigate the molecular etiology of IPMNs and PDACs at different histopathological grades, finding that the mutational processes observed in each are markedly alike, suggesting instead that microenvironmental and epistatic dynamics of the heterogenous proto-tumor drive progression. Finally, to detail prospective mutational trajectories by which IPMNs progress to KRAS-positive PDACs, we leverage selective epistatic interactions to map likely mutational orderings in PDACs and compare those orderings to the sequence of mutations reconstructed via phylogenetic analysis of IPMN lineages. Citation Format: Derek C. Song, Nic Fisk, Margaret Moore, Vincent L. Cannataro, Jeffrey D. Mandell, Luisa Escobar-Hoyos, Leanne Brown, Lu Qiao, John W. Kunstman, Jeffrey P. Townsend. Evolutionary trajectories inferred by selective epistasis and phylogenetic analysis reveal the malignant progression of intraductal papillary mucinous neoplasms to pancreatic ductal adenocarcinoma [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 7496.