Background: Rare variants play an essential role in the etiology of cancer. In this study, we aim to characterize rare germline variants that impact the risk of cancer. Methods: We performed a genome-wide rare variant analysis using germline whole exome sequencing (WES) data derived from the Geisinger MyCode initiative to discover cancer predisposition variants. The case–control association analysis was conducted by binning variants in 5,538 patients with cancer and 7,286 matched controls in a discovery set and 1,991 patients with cancer and 2,504 matched controls in a validation set across nine cancer types. Further, The Cancer Genome Atlas (TCGA) germline data were used to replicate the findings. Results: We identified 133 significant pathway–cancer pairs (85 replicated) and 90 significant gene–cancer pairs (12 replicated). In addition, we identified 18 genes and 3 pathways that were associated with survival outcome across cancers (Bonferroni P < 0.05). Conclusions: In this study, we identified potential predisposition genes and pathways based on rare variants in nine cancers. Impact: This work adds to the knowledge base and progress being made in precision medicine.

中文翻译：

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来自电子健康记录关联生物库的九种癌症类型的功能性罕见种系变异的遗传分析

背景：罕见变异在癌症的病因学中起着至关重要的作用。在这项研究中，我们旨在表征影响癌症风险的罕见种系变异。方法：我们使用来自 Geisinger MyCode 计划的生殖系全外显子组测序 (WES) 数据进行了全基因组罕见变异分析，以发现癌症易感性变异。病例-对照关联分析是通过对发现集中的 5,538 名癌症患者和 7,286 名匹配对照以及在九种癌症类型的验证集中对 1,991 名癌症患者和 2,504 名匹配对照进行分箱来进行的。此外，癌症基因组图谱（TCGA）种系数据被用来复制这些发现。结果：我们确定了 133 个重要的通路-癌症对（85 个重复）和 90 个重要的基因-癌症对（12 个重复）。此外，我们确定了与癌症生存结果相关的 18 个基因和 3 个通路（Bonferroni P < 0.05）。结论：在这项研究中，我们根据九种癌症的罕见变异确定了潜在的易感基因和途径。影响：这项工作增加了精准医学的知识库和进展。