Clinicogenomic landscape of IPMN-derived pancreatic cancer

Further understanding of the genomic alterations in intraductal papillary mucinous neoplasm (IPMN)- derived pancreatic cancer and associations with survival outcomes is necessary to identify tailored therapy and improve outcomes. We reviewed resected IPMN-associated pancreatic cancer cases from 2012 to 2025 and identified cases of pancreatic ductal adenocarcinoma (PDAC) where pathology demonstrated that the invasive component arose from an IPMN (not concomitant PDAC). 38 patients with corresponding comprehensive genomic profiling results were identified and clinical characteristics and outcomes data were collected. 30 patients (79%) had KRAS mutated (mt) and 8 patients (21%) had KRAS wild type (WT) tumors. 12 tumors (32%) were mtGNAS and 26 tumors (68%) were GNAS WT. Further examining mtKRAS in the context of mtGNAS, 23 patients' tumors (61%) had mtKRAS alone, 7 (18%) with KRAS and GNAS co-mutation, 5 (13%) with mtGNAS alone, and 3 patients (8%) had neither mutation. KRAS wild type (WT) tumors associated with better overall survival (OS) and disease-free survival (DFS) compared with mtKRAS tumors. mtGNAS tumors associated with better DFS compared with GNAS WT tumors. In the 5 mtGNAS-only tumors, there was an enrichment of CCND2 and MYC gene family co-amplifications (3 out of 5). The other two mtGNAS-only cases had BRAF and MAP2K1 (MEK) mutations. 7 cases (18%) harbored ATM mutations and 2 cases (5%) of RNF43 mutations were identified. In univariate cox regression analysis, only lymphovascular invasion (LVI) was significantly associated with OS. LVI and node positivity were significantly associated with DFS. Despite limited numbers of patients, we have identified KRAS WT and mtGNAS as potential prognostic biomarkers for IPMN-derived PDAC.