Kyle M. Hernandez1,11, Aarti Venkat2,3,11, Danne C. Elbers4,5,6,11, John R. Bihn4, Mary T. Brophy4,6, Nhan V. Do4,6, Jennifer La4,5, Qiong Liu7, Andrew Prokhorenkov3, Noah Metoki-Shlubsky3, Feng-Chi Sung4, Channing J. Paller8,12, Nathanael R. Fillmore4,5,9,12 and Robert L. Grossman2,3,10,12 1Belay Diagnostics, Chicago, Illinois 60607, USA; 2Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA; 3Center for Translational Data Science, University of Chicago, Chicago, Illinois 60637, USA; 4VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts 02130, USA; 5Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA; 6Chobanian and Avedisian School of Medicine, Boston University, Boston, Massachusetts 02118, USA; 7Frederick National laboratory for Cancer Research, Frederick, Maryland 21701, USA; 8The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 9Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; 10Open Commons Consortium, Chicago, Illinois 60611, USA Corresponding authors: cpaller1jhmi.edu; nathanael.fillmoreva.gov; rgrossman1uchicago.edu

↵11 Co-first authors.

↵12 Co-corresponding authors.

Abstract

Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared with the general population. However, little is known about the underlying molecular heterogeneity within the veteran population and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the National Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration-resistant. We characterized the mutational burden in this cohort and conducted unsupervised clustering analysis to stratify patients by molecular alterations. Veterans with prostate cancer exhibited a mutational landscape broadly similar to prior studies, including KMT2A and NOTCH1 mutations associated with neuroendocrine prostate cancer phenotype, previously reported to be enriched in veterans. We also identified several potential novel mutations in PTEN, MSH6, VHL, SMO, and ABL1. Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.

Received June 6, 2023. Accepted October 31, 2023.

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