We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10-6; exome-wide statistical significance threshold P < 2.5x10-6). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35; P = .045). At the suggestive threshold (P < .001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition.

中文翻译：

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胰腺癌风险的全外显子组关联研究。

我们进行了一项病例对照全外显子组关联研究，结合 5 项研究的数据，发现编码区中影响胰腺癌风险的种系变异。我们分析了 437 名胰腺癌患者（病例）和 1922 名未知癌症患者（对照）的外显子组和基因组测序数据。在初步分析中，BRCA2 对罕见失活变异的富集程度最高（17/437 例病例 vs 3/1922 对照）（P = 3.27x10-6；全外显子组统计显着性阈值 P < 2.5x10-6）。即使排除了已知易患胰腺癌的 13 个基因，病例中的 DNA 修复基因失活变异也比对照组更多（调整后的比值比为 1.35；P = 0.045）。根据序列-内核关联，在建议阈值 (P < .001) 下，6 个基因富集了罕见的破坏性变异（UHMK1、AP1G2、DNTA、CHST6、FGFR3 和 EPHA1），7 个基因与胰腺癌风险相关测试。我们确认 BRCA2 变异是与胰腺癌相关的最常见的高渗透遗传因子，并且我们还确定了候选胰腺癌基因。需要大规模合作和新方法来克服胰腺癌易感性的遗传异质性。