Abstract B035: Integrative multi-omics and microbiome profiling reveals molecular and microbial heterogeneity in a diverse cohort of pancreatic ductal adenocarcinoma
Francisco G. Carranza, Brigette Waldrup, Sophia Manjarrez, Vincent Chung, Laleh Melstrom, Steven T. Rosen, Enrique Velazquez-VillarrealAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by extensive molecular heterogeneity and persistent disparities in clinical outcomes. Despite recent advances in genomic profiling, the molecular and microbial factors underlying disease heterogeneity across genetically diverse populations and age at diagnosis remain incompletely understood.
Methods:
We performed an integrative multi-omics analysis of 77 primary PDAC tumors from a diverse patient cohort from City of Hope Precision Oncology Software Environment Interoperable Data Ontologies Network (POSEIDON). Whole-exome sequencing was used to identify somatic mutations, copy number alterations, mutational burden, and genetic similarity (ancestry). RNA sequencing characterized differential gene expression, pathway dysregulation, and oncogenic gene fusions, while tumor-associated microbiome profiles were inferred from sequencing data to investigate microbial signatures associated with pancreatic tumor biology. Genomic frequencies findings were compared with publicly available PDAC datasets to identify population-specific and clinically relevant molecular features.
Results:
Comprehensive genomic profiling identified recurrent PDAC driver alterations in each of the five superpopulations according with the 1000 Genome project. Approximately 12% of tumors were classified as hypermutated, predominantly among patients genetically assigned to the East Asian ancestry group and diagnosed after 50 years of age. Notably, SOX9 alterations were recurrent within hypermutated tumors, suggesting a potential role in this molecular subtype. Early-onset PDAC (<50 years old) exhibited a higher frequency of KRAS alterations compared with late-onset disease (>=50 years old), whereas transcriptomic analyses identified significant downregulation of ITGB8 and FGF1. Copy number analyses revealed multiple focal amplifications, including potentially druggable genomic events, while RNA sequencing identified numerous gene fusions across both early- and late-onset tumors. Finally, tumor-associated microbiome profiling demonstrated distinct microbial communities between early- and late-onset PDAC, suggesting that microbial composition may contribute to age-associated biological differences.
Conclusions:
Integrative genomic, transcriptomic, and microbiome profiling reveals substantial molecular and microbial heterogeneity across a diverse cohort of PDAC patients. These findings identify ancestry-, age-, and subtype-associated molecular features that complement publicly available datasets, expand our understanding of pancreatic cancer biology, and provide a resource for biomarker discovery and precision oncology strategies in this highly aggressive malignancy.
Citation Format:
Francisco G. Carranza, Brigette Waldrup, Sophia Manjarrez, Vincent Chung, Laleh Melstrom, Steven T. Rosen, Enrique Velazquez-Villarreal. Integrative multi-omics and microbiome profiling reveals molecular and microbial heterogeneity in a diverse cohort of pancreatic ductal adenocarcinoma [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 B035.