Abstract A066: Toward early detection of pancreatic cancer: Somatic genomic profiling of early- and late-onset PDAC in a diverse cohort
Brigette Waldrup, Francisco G. Carranza, Sophia Manjarrez, Vincent Chung, Laleh Melstrom, Steven T. Rosen, Enrique Velazquez-VillarrealAbstract
Background:
The incidence of early-onset pancreatic ductal adenocarcinoma (EO-PDAC) is increasing, yet its molecular characteristics remain poorly defined. Improved understanding of genomic alterations associated with EO-PDAC may facilitate the discovery of biomarkers for earlier detection and precision oncology. We aimed to characterize the somatic genomic landscape of early- (<50 years of age) and late-onset (>=50 years of age) PDAC in a diverse cohort and identify genomic alterations with potential relevance for early detection.
Methods:
A total of 1,824 pancreatic ductal adenocarcinoma (PDAC) molecular profiles were analyzed, including 127 early-onset and 1,697 late-onset cases. Among these, 77 PDAC tumors with available self-reported race/ethnicity were obtained from the City of Hope POSEIDON system. This institutional cohort comprised 39 White non-Hispanic or Latino (50.6%), 18 Asian (23.4%), 14 White Hispanic or Latino (18.2%), and 6 Black or African American (7.8%) patients. Paired whole-exome sequencing (WES) was performed on tumor and matched benign tissues from these cases to identify somatic genomic alterations. To enhance statistical power and validate the findings, these data were integrated with publicly available PDAC genomic datasets. Bioinformatic analyses included somatic mutation profiling, genetic ancestry inference, and comparative analyses of the genomic landscapes of early-onset and late-onset PDAC.
Results:
Across the cohort, genetic ancestry (or genetic similarity, following the terminology recommended by the National Academies of Sciences, Engineering, and Medicine (NASEM)) inference demonstrated high concordance with self-reported race/ethnicity. Most patients were assigned to the same ancestral group based on the highest genetic similarity to one of the five 1000 Genomes Project superpopulations. The most frequently altered genes were KRAS, TP53, and SMAD4, consistent with established PDAC biology. Compared with predominantly non-Hispanic White public datasets, our cohort demonstrated significantly higher mutation frequencies in KRAS, TP53, CDKN2A, SMAD4, BRCA1, RREB1, TGFBR2, PALB2, and MYC. Comparative analyses between EO- and LO-PDAC identified significant differences in KRAS mutation frequencies. Furthermore, the prevalence of the KRAS G12D substitution was significantly enriched compared with public reference datasets, highlighting a candidate genomic feature that warrants further investigation as a potential biomarker for risk stratification & earlier disease detection.
Conclusions:
Somatic genomic profiling of a diverse PDAC cohort revealed a conserved mutational landscape while identifying genomic differences between early- and late-onset disease and relative to publicly available datasets. These findings provide preliminary evidence that age-associated genomic biomarkers may improve PDAC risk assessment, facilitate earlier detection, and advance precision oncology. Larger multi-institutional studies are needed to validate these observations and identify clinically actionable biomarkers for early diagnosis.
Citation Format:
Brigette Waldrup, Francisco G. Carranza, Sophia Manjarrez, Vincent Chung, Laleh Melstrom, Steven T. Rosen, Enrique Velazquez-Villarreal. Toward early detection of pancreatic cancer: Somatic genomic profiling of early- and late-onset PDAC in a diverse cohort [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A066.