Abstract Background: How germline and somatic alterations together contribute to alterations in cancer relevant pathways in individual cancers remains poorly understood. Methods: We mapped all germline and somatic alterations of individual cancer samples from The Cancer Genome Atlas (TCGA) and the Breast Cancer Genome Guided Therapy Study (BEAUTY) onto Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) pathways. To quantify pathway-level disturbances from germline and somatic origins, we calculated gene-level impact scores by integrating the functional importance of a gene in sustaining cell survival with the predicted impact of its variants. These scores were then used to compute a pathway disturbance score (CanSys score), that quantified the combined effect of gene-level alterations across all pathway members. Results: We found that almost all cancers have common and rare protein function altering germline alterations in cell cycle, telomere maintenance, and DNA repair hallmark pathways. At somatic mutation level, 12 pathways were altered in 75% of cancers corresponding to core cancer hallmarks, however different genes within the same pathway are affected in different individuals, illustrating phenotypic convergence. In addition, 404 pathways were affected in 25% but 50% of cancers which may contribute to the unique clinical course of each cancer. A freely available web tool (https://cansysplot.com) developed for this study enables visualization of GO/KEGG pathway disturbances from germline and somatic origins at the individual sample level. Conclusion: Our findings implicate that the individuals with cancer harbor protein function altering germline alterations in genes involved with cell cycle regulation, telomere maintenance, and DNA repair, whereas somatic mutations primarily affect pathways involved in cell adhesion, cell motility, metabolism, and a broad range of signal transduction processes. The unique combination of pathway alterations might explain the unique behavior of each cancer. Citation Format: J. Dai, M. Posta, M. Marczyk, T. Qing, B. Győrffy, L. Pusztai. Common and rare germline variants together with somatic mutations alter the integrity of cancer hallmark regulatory networks abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-04-24.
Dai et al. (Tue,) studied this question.