Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study

Familial Pancreatic Cancer (FPC) is responsible for up to 10% of all cases of pancreatic ductal adenocarcinoma (PDAC). Individuals predisposed for FPC have an estimated lifetime risk of 16–39% of developing PDAC. While heritability of PDAC has been estimated to be 36% in a Nordic twin study, no heritability estimate specific on FPC has been reported. A national cohort of Danish families with predisposition for FPC is currently included in a screening program for PDAC at Odense University Hospital. Family members included in the screening program were interviewed for pedigree data including: cases of PDAC among first-degree relatives (FDRs) and number of affected/unaffected siblings. Heritability for FPC in the predisposed families was assessed by doubling the estimated intra-class correlation coefficient (ICC) from a random intercept logistic model fitted to data on FDRs. Among families with predisposition for FPC, 83 cases of PDAC were identified. The median age at diagnosis of PDAC was 66 years, and median time from diagnosis to death was 7.6 months. A total of 359 individuals were found as unaffected FDRs of the 83 PDAC cases. The retrieved FDRs included a total of 247 individuals in sibship and 317 individuals in parent-offspring relatedness. We estimated an ICC of 0.25, corresponding to a narrow sense additive heritability estimate of 0.51 in the FPC family cohort. We have established a nation-wide cohort of FPC families to facilitate clinical and genetic studies on FPC. The estimated heritability of 51% prominently underlines a strong genetic background of FPC.家族性胰腺癌（Familial Pancreatic Cancer, FPC）约占全部胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma, PDAC）病例的10%。据估计，携带FPC易感倾向的个体终生罹患PDAC的风险为16%~39%。既往一项北欧双生子研究估算PDAC的遗传力为36%，但目前尚无针对FPC的特异性遗传力评估报道。目前，丹麦全国范围内携带FPC易感倾向的家庭队列，已纳入欧登塞大学医院开展的PDAC筛查项目。本研究对纳入该筛查项目的家庭成员进行了家系数据访谈，采集的信息包括一级亲属（First-Degree Relatives, FDRs）中的PDAC发病情况，以及受累与未受累同胞的数量。研究通过对一级亲属数据拟合随机截距logistic模型得到的组内相关系数（Intra-Class Correlation Coefficient, ICC）翻倍，以此计算易感FPC家庭的FPC遗传力。在携带FPC易感倾向的家庭中，共检出83例PDAC患者。该队列中PDAC患者的诊断中位年龄为66岁，从确诊至死亡的中位时间为7.6个月。在这83例PDAC患者中，共确认359名未受累的一级亲属。其中，同胞关系亚组包含247名个体，亲子关系亚组包含317名个体。本研究估算得到的ICC为0.25，对应该FPC家庭队列的狭义加性遗传力为0.51。本研究已建立全国性FPC家庭队列，以推动FPC的临床与遗传学相关研究。本次得到的51%遗传力估算值，显著证实了FPC具有较强的遗传背景。