Campa Daniele, Pastore Manuela, Gentiluomo Manuel, Talar-Wojnarowska Renata, Kupcinskas Juozas, Malecka-Panas Ewa, Neoptolemos John P, Niesen Willem, Vodicka Pavel, Delle Fave Gianfranco, Bueno-de-Mesquita H Bas, Gazouli Maria, Pacetti Paola, Di Leo Milena, Ito Hidemi, Klüter Harald, Soucek Pavel, Corbo Vincenzo, Yamao Kenji, Hosono Satoyo, Kaaks Rudolf, Vashist Yogesh, Gioffreda Domenica, Strobel Oliver, Shimizu Yasuhiro, Dijk Frederike, Andriulli Angelo, Ivanauskas Audrius, Bugert Peter, Tavano Francesca, Vodickova Ludmila, Zambon Carlo Federico, Lovecek Martin, Landi Stefano, Key Timothy J, Boggi Ugo, Pezzilli Raffaele, Jamroziak Krzysztof, Mohelnikova-Duchonova Beatrice, Mambrini Andrea, Bambi Franco, Busch Olivier, Pazienza Valerio, Valente Roberto, Theodoropoulos George E, Hackert Thilo, Capurso Gabriele, Cavestro Giulia Martina, Pasquali Claudio, Basso Daniela, Sperti Cosimo, Matsuo Keitaro, Büchler Markus, Khaw Kay-Tee, Izbicki Jakob, Costello Eithne, Katzke Verena, Michalski Christoph, Stepien Anna, Rizzato Cosmeri, Canzian Federico
Department of Biology, University of Pisa, Pisa, Italy.
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncotarget. 2016 Aug 30;7(35):57011-57020. doi: 10.18632/oncotarget.10935.
The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.
CDKN2A（p16）基因在胰腺癌病因学中起关键作用。它是胰腺癌中最常见的体细胞突变基因之一，已发现罕见的种系突变与家族性胰腺癌发病风险增加有关，并且有人提出CDKN2A启动子高甲基化在胰腺癌的发生和预后中均起关键作用。此外，9p21.3区域中的几个不相关的单核苷酸多态性（SNP），包括CDNK2A、CDNK2B和CDNK2B-AS1基因，与各种器官癌症的发生有关。然而，该区域常见基因变异性与胰腺癌风险之间的关联尚不清楚。我们试图在一项病例对照研究中填补这一空白，该研究在胰腺疾病研究（PANDoRA）联盟的背景下，对2857例胰腺导管腺癌（PDAC）患者和6111例对照进行了13个单核苷酸多态性（SNP）的基因分型。我们发现rs3217992 SNP的A等位基因与胰腺癌风险增加相关（ORhet=1.14，95%CI 1.01-1.27，p=0.026，ORhom=1.30，95%CI 1.12-1.51，p=0.00049）。据报道，这种多效性变异是一种mir-SNP，通过改变一种或多种miRNA的结合位点，可能影响正常细胞周期进程，进而增加PDAC风险。总之，我们在一个多效性区域观察到一种新的关联，该区域已被发现与各种类型癌症和糖尿病的易感性密切相关，这表明CDKN2A/B基因座可能代表糖尿病与胰腺癌风险之间的遗传联系。
