BACKGROUND While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. METHODS We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. RESULTS We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. CONCLUSIONS Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.

中文翻译：

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10,582 名患者的预后种系变异的泛癌景观。

背景虽然诸如年龄、等级、分期和组织学亚型等临床因素为医生提供了有关患者预后的信息，但基因组数据可以进一步改进这些预测。先前的研究表明，已知癌症驱动基因中的种系变异可以预测患者的预后，但没有研究以公正的方式系统地分析多种癌症，以确定可以改善使用临床因素做出的患者预后预测的基因位点。方法 我们分析了通过癌症基因组图谱获得的超过 10,000 名癌症患者的测序数据，以使用多变量 Cox 回归模型识别与患者预后相关的种系变异。结果 我们在个体癌症中鉴定了 79 种预后生殖系变异体，在癌症组中鉴定了 112 种预后生殖系变异体。在个体癌症中鉴定的种系变异提供了超出当前使用的临床信息的关于患者结果的额外预测能力，因此可能会根据预期的肿瘤侵袭性增强临床决策。在分子上，至少 12 个种系变体可能通过蛋白质结构的扰动与患者结果相关，至少 5 个通过与基因表达差异相关联。这些种系变异中几乎有一半存在于先前报道的肿瘤抑制基因、癌基因或癌症驱动基因中，另一半指向基因组位点，应进一步研究它们在癌症中的作用。结论 种系变异可以预测癌症患者的结果，特定的种系变异可以改善患者的结果预测，超出仅使用临床因素做出的预测。种系变异还暗示已知癌基因、肿瘤抑制基因和驱动基因在癌症中受到干扰的新方法，并暗示了其他尚未在肿瘤学中广泛研究的基因在癌症中的作用。有必要在其他癌症队列中进行进一步的研究，以确认种系变异与癌症患者的结果相关，因为这是一项原理验证研究。和驱动基因在癌症中受到干扰，并提示其他尚未在肿瘤学中广泛研究的基因在癌症中的作用。有必要在其他癌症队列中进行进一步的研究，以确认种系变异与癌症患者的结果相关，因为这是一项原理验证研究。和驱动基因在癌症中受到干扰，并提示其他尚未在肿瘤学中广泛研究的基因在癌症中的作用。有必要在其他癌症队列中进行进一步的研究，以确认种系变异与癌症患者的结果相关，因为这是一项原理验证研究。