First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were over-represented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.

中文翻译：

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全基因组测序鉴定了家族性胰腺癌患者一级亲属中富含癌症相关基因的罕见种系变异

家族性胰腺癌 (FPC) 患者的一级亲属 (FDR) 患胰腺导管腺癌 (PDAC) 的风险增加。调查和了解 FPC 易感家庭中 PDAC 易感性的遗传基础可能有助于未来的风险评估和高风险个体的管理。使用丹麦的 27 个 FPC 家族队列，我们​​对 61 个 FPC 患者的 FDR 进行了全基因组测序，重点关注可能导致 PDAC 家族聚集的罕见遗传变异。使用 gnomAD 数据库作为外部对照进行统计分析。通过对杂合过早截断变异体 (PTV) 的分析，我们确定了具有多个种系突变的癌症相关基因和癌症驱动基因。关联分析检测到 20 个具有错误发现率的显着基因，PALD1 , LRP1B , COL4A2 , CYLC2 , ZFYVE9 , BRD3 , AHDC1等。功能注释显示重要基因被编码细胞外基质和相关蛋白的基因簇富集。PTV 基因被与小分子转运、先天免疫系统、离子通道转运和刺激传感通道相关的功能过度代表。总之，FPC 患者的 FDR 携带与癌症发病机制相关的罕见种系变异，这可能有助于增加对 PDAC 的易感性。确定的变异可能对易感家庭中高风险个体的风险预测有用。