胰腺导管腺癌(PDAC)是全球癌症死亡的第七大原因;大多数病例是散发性的,然而,约有5%至10%的人报告有遗传倾向。一些遗传性综合征与家族性胰腺癌(FPC)发病有关,包括遗传性乳腺癌和卵巢癌综合征(HBOC),林奇综合征(LS),家族性非典型多发性痣黑色素瘤(FAMMM),家族性腺瘤性息肉病(FAP),Li-Fraumeni综合征(LFS),Peutz-Jeghers综合征(PJS),和遗传性胰腺炎(HP)。这项研究的目的是确定56个HBOC家族的突变状态,7个LS家庭,3个FAP和FAMMM系列,和1个LFS家族,至少1例PDAC。BRCA1/2,ATM,CHEK2,PALB2,RAD51C,RAD51D,NBN,CDH1,TP53,MLH1,MSH2,MSH6和PMS2基因,显示BRCA1/2、MLH1和APC基因的突变。我们发现HBOC和LS家族患者的突变率很高,BRCA2突变的HBOC的两种证型和患病率均占28.6%,其中1例BRCA2基因双突变。在FAP家族中,我们在1/3家族的APC基因中发现了致病突变。我们观察到PDAC的早期发作和属于突变家族的PDAC患者的较低生存率。而没有发现可能的胰腺癌聚集区域的证据。此外,我们发现了一个新的BRCA2种系突变,c.5511delT(p.Phe1837LeufsX3),没有在任何数据库中报告,与HBOC患者的疾病隔离。突变分析扩展到突变患者的家庭成员,健康和癌症都受影响,这揭示了23个未受影响的家族成员继承了先证者的突变。虽然从本质上来说是相关的,PDAC患者中存在BRCA突变可能在优化治疗和延长结局方面获益.
Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband\'s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.