Abstract B075: Young- and older-onset pancreatic cancers arise through distinct mechanisms: Insights from genomic and germline analyses

Abstract INTRODUCTION: Young-onset pancreatic cancer is increasing in incidence. Age is the strongest risk factor for pancreatic cancer; yet, tobacco smoking and inherited genetic factors are known to influence disease risk, particularly in younger individuals. METHODS: To investigate how aging, tobacco exposure, and inherited susceptibility contribute to disease onset, we analyzed germline and somatic whole-genome, whole-exome, and targeted exome sequencing data from 1000 patients with pancreatic cancer across multiple cohorts from local and publicly available datasets. Mutational signature analyses quantified endogenous (e. g. , aging-related) and exogenous (e. g. , tobacco-related) mutational processes, which were assessed by age at diagnosis and smoking status. In a subset of tumors with DNA methylation data, we applied an epigenetic mitotic clock to estimate stem cell division rates based on age-related methylation at CpG-rich promoters. We also identified pathogenic or likely pathogenic (P/LP) germline variants in 21 pancreatic cancer risk genes using ClinVar annotations, evaluated somatic second hits in matched tumors, and calculated a weighted polygenic risk score (PRS) from 22 known low-penetrance susceptibility variants, defining a higher PRS as above the median in healthy individuals. RESULTS: In non-hypermutated tumors, total somatic mutation burden significantly increased with age, primarily driven by clock-like signatures (e. g. , SBS1, SBS5, ID1, ID2, ID5). These signatures accounted for an estimated 78% of mutations in older-onset cases (60 years), increasingly accounting for mutations in main driver genes (KRAS, CDKN2A, SMAD4, TP53). In contrast, smoking-related mutational changes were exclusive to young-onset cases (≤60 years). Young-onset smokers had elevated mutation burdens despite lacking the canonical tobacco signature (SBS4), instead showing increased SBS1 and ID2 signatures, linked to stem cell divisions and DNA replication, as well as higher stem cell division rates inferred from epigenomic analyses. Young smokers also had higher frequencies of TP53 mutations compared to non-smokers (83% vs. 64%; P=. 001), particularly missense mutations at CpG sites. Additionally, P/LP germline variants were more frequent in young-onset than older-onset cases (13% vs. 7%; P=. 002), with enrichment most evident for BRCA2, and contributed to younger onset only when accompanied by a somatic second hit. A higher PRS was modestly associated with reduced median age of cancer onset (by 4 years), with greater reductions when combined with smoking (7 years earlier) or P/LP variants (14 years earlier), compared to patients with neither of these factors. CONCLUSIONS: Our findings support a multifactorial model for pancreatic cancer development: aging-related mutational processes drive older-onset disease, while young-onset disease is more strongly influenced by environmental and inherited factors. These insights have important implications for risk stratification and interception strategies across age groups. Citation Format: Chen Yuan, Harshabad Singh, Kevin S. Kapner, Andressa Dias Costa, Anuradha B. Chittenden, Xinran Qi, Vidya Madineedi, Leigh Culnane, Lauren K. Brais, Douglas A. Rubinson, James M. Cleary, Brandon M. Huffman, Joseph D. Mancias, Thomas E. Clancy, Simona Cristea, Kimmie Ng, Matthew B. Yurgelun, David C. Linehan, Richard F. Dunne, Albert C. Koong, Daniel T. Chang, Aram F. Hezel, Andrew J. Aguirre, Jonathan A. Nowak, Brian M. Wolpin. Young- and older-onset pancreatic cancers arise through distinct mechanisms: Insights from genomic and germline analyses abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B075.