体细胞突变推动癌症的发展，并与患者治疗反应有关。新兴证据显示，体细胞基因组的变异可以受种系遗传背景的影响。然而，这些种系-体细胞关联的机制仍然大多不为人知。我们假设种系变异可以通过对基因表达的调控作用，影响靠近癌症基因（“局部作用”）或整个基因组中经常突变的癌症基因集（“全局作用”）的体细胞突变。为了验证这一假设，在 Dana-Farber Profile 资料库中，将来自 Genotype-Tissue Expression Project 的种系癌症基因表达数量性状位点（eQTL）与来自 11 种癌症类型的 12,413 名患者的肿瘤定向测序数据进行整合。发现通过上调 ATM 的表达量可以降低 8 种癌症类型中 ATM 的体细胞突变风险。在卵巢癌、胶质瘤和食管胃癌中，GLI2、WRN 和 CBFB 的 eQTL 与全局肿瘤突变负荷的癌症基因相关。一个 EPHA5 的 eQTL 与结直肠癌特异的癌症基因突变相关，与 APC、WRN、GLI1、FANCA 和 TP53 表达有关的 eQTL 与特异性的子宫内膜癌基因突变相关。这些发现提供了证据，说明种系-体细胞关联是通过特定癌症基因的表达介导的，为了解其潜在的生物过程，开辟了新的研究途径。

Somatic mutations drive cancer development and are relevant to patient responses 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. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline-somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes.