Functional germline variants together with somatic mutations alter the integrity of cancer hallmark regulatory networks

Background: How germline and somatic alterations together contribute to alterations in cancer relevant pathways in individual cancers remains poorly understood. In this study, we provide a quantitative framework to characterize their contributions to pathway-level disturbances in individual cancers. Methods: We mapped germline and somatic DNA alterations of individual cancer samples from The Cancer Genome Atlas (TCGA), the Breast Cancer Genome Guided Therapy Study (BEAUTY) and the East Asian-ancestry Lung Adenocarcinoma (EAS-LUAD) cohort onto Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (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 more than 10% of TCGA cancers have 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. Conclusions: Our findings indicate that a substantial proportion of 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.