Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.

人类癌症由环境、遗传和体细胞因素引起，但人们对这些机制在肿瘤发生中如何相互作用知之甚少。研究人员对 17,152 名癌症患者进行了前瞻性测序，确定了癌症易感基因中的致病性种系变异，并评估了它们的接合性和伴随肿瘤中同时发生的体细胞改变。肿瘤发生的两条主要途径是显而易见的。在高外显率基因致病性种系变异的携带者中（总体为 5.1%），谱系依赖性双等位基因失活模式导致肿瘤表现出机制特异性的体细胞表型和更少的额外体细胞致癌驱动因素。然而，这些患者中 27% 的癌症，以及外显率较低的基因中具有致病性种系变异的患者中的大多数肿瘤，缺乏与种系等位基因相关的肿瘤发生的特定标志。肿瘤对致病种系变异的依赖性是可变的，并且通常由外显率和谱系决定，这一发现对临床管理具有影响。