Germline Cancer Gene Expression Quantitative Trait Loci Influence Local and Global Tumor Mutations

Somatic mutations drive cancer development and are relevant to patients’ response to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline-somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene (“local impact”) or a set of recurrently mutated cancer genes across the genome (“global impact”) through their regulatory effect on gene expression. We integrated tumor targeted sequencing from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. We identified variants that upregulate ATM expression which are also associated with a decreased risk of having somatic ATM mutations across 8 cancer types ( P = 3.43 × 10−5). We also identified GLI2, WRN , and CBFB eQTL that are associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively ( P < 3.45 × 10−6). An EPHA5 eQTL was associated with the number of mutations in cancer genes specific to colorectal cancer, and eQTL associated with expression of APC, WRN, GLI1, FANCA , and TP53 were associated with mutations in genes specific to endometrial cancer ( P < 1.73 × 10−5). Our findings provide evidence for the germline-somatic associations mediated through expression of specific cancer genes and open new avenues for research on the underlying biological processes, especially those related to immunotherapy responses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Cancer Institute grants R01CA227237 and R01CA244569 (to A. Gusev), and R01CA260352 (to P. Kraft), Phi Beta Psi Sorority, and Emerson Collective ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Dana-Farber/Partners Cancer Care Office for the Protection of Research Subjects gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The individual-level data used in this study are not publicly available due to patient privacy requirements. Other unidentifiable data generated in this study are available within the article and its supplementary data files