BACKGROUND The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. METHODS Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. FINDINGS Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. INTERPRETATION The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. FUNDING This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).

中文翻译：

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对家族性胰腺癌家族候选基因的全面分析揭示了潜在致病性种系变异的高频率。


背景技术胰腺导管腺癌（PDAC）患者的 5 年生存率约为 5%，因为大多数患者都患有治疗耐药的晚期疾病。家族性胰腺癌 (FPC) 是一种罕见疾病，定义为至少有两名一级亲属受影响的家庭，估计发病率为 4%-10%。尽管大约 10%-13% 的家庭携带与遗传性癌症和胰腺炎综合征相关的已知基因的种系突变，但大多数家庭的遗传基础尚不清楚。方法 对来自具有明显遗传性胰腺癌综合征家族的 43 例 PDAC 病例中的 35 个与遗传性癌症相关的基因进行了面板测序。结果 在纯 FPC 家族的 19% (5/26) 的 PDAC 病例中，在基因 MLH1、CDKN2A、POLQ 和 FANCM 中发现了致病性变异。在来自 FPC 家族的 35% (9/26) 的 PDAC 病例中，在 FANCC、MLH1、PMS2、CFTR、APC 和 MUTYH 基因中也发现了低频潜在致病性 VUS。此外，很大一部分 PDAC 病例携带不止一种致病性、可能致病性或潜在致病性 VUS，凸显了 FPC 的多基因表型。解释 21% 的家族中家族性或遗传性胰腺癌的遗传基础可以通过先前描述的遗传性癌症基因来解释。 35% 的家庭中也存在其他 DNA 修复基因的低频变异，这可能会增加患胰腺癌的风险。 资助 本研究由 Instituto de Salud Carlos III（Plan Estatal de I + D + i 2013-2016）资助：ISCIII（PI09/02221、PI12/01635、PI15/02101 和 PI18/1034），并由欧洲发展区域基金“实现欧洲的途径”(ERDF)、癌症生物医学研究网络：CIBERONC (CB16/12/00446)、癌症合作研究红色专题：RTICC (RD12/0036/0073) 和西班牙抗癌协会：AECC（Grupos Coordinados Estables 2016）。