biostudies-literatureTaraszka KDoris Duke Charitable FoundationNIEHS NIH HHSNHLBI NIH HHSU.S. Department of DefenseNHGRI NIH HHSNCI NIH HHSEmerson CollectiveNational Institutes of HealthChan Zuckerberg Initiative242-258https://www.ebi.ac.uk/biostudies/studies/S-EPMC10870141biostudies-literatureUnknown111(2)Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available. We report dozens of clinical associations with TMB/CNB, observing older age and male sex to have a strong effect on TMB and weaker impact on CNB. We additionally identified significant germline influences on TMB/CNB, including fine-scale European ancestry and germline polygenic risk scores (PRSs) for smoking, tanning, white blood cell counts, and educational attainment. We quantify the causal effect of exposures on somatic mutational processes using Mendelian randomization. Many of the identified features associated with TMB/CNB were additionally associated with OS for individuals treated at a single tertiary cancer center. For individuals receiving immunotherapy, we observed a complex relationship between PRSs for educational attainment, self-reported college attainment, TMB, and survival, suggesting that the influence of this biomarker may be substantially modified by socioeconomic status. While the accumulation of somatic alterations is a stochastic process, our work demonstrates that it can be shaped by host characteristics including germline genetics.American journal of human geneticsA comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.PMC10870141U01HG009080R01CA227237R01 CA244569U01 HG009080W81XWH-16-2-0018K25 HL121295R01 HG006399R01ES029929R01 HG011345R01HG011345K25HL121295R01 CA262577R01HG006399R01 ES029929R01CA244569R01 CA227466R01CA262577R01 CA227237White KGusev AZaitlen NTaraszka KZiv ETell RKing DGroha SfalseA comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available. We report dozens of clinical associations with TMB/CNB, observing older age and male sex to have a strong effect on TMB and weaker impact on CNB. We additionally identified significant germline influences on TMB/CNB, including fine-scale European ancestry and germline polygenic risk scores (PRSs) for smoking, tanning, white blood cell counts, and educational attainment. We quantify the causal effect of exposures on somatic mutational processes using Mendelian randomization. Many of the identified features associated with TMB/CNB were additionally associated with OS for individuals treated at a single tertiary cancer center. For individuals receiving immunotherapy, we observed a complex relationship between PRSs for educational attainment, self-reported college attainment, TMB, and survival, suggesting that the influence of this biomarker may be substantially modified by socioeconomic status. While the accumulation of somatic alterations is a stochastic process, our work demonstrates that it can be shaped by host characteristics including germline genetics.2024-01-01T00:00:00Z2024 Feb2026-03-31T11:04:55.874Z2025-08-27T03:10:55.341ZS-EPMC108701413821158510.1016/j.ajhg.2023.12.010