Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

被引：42

作者：

Campa, Daniele ^{[1
,2
]}

Pastore, Manuela ^{[1
,2
]}

Gentiluomo, Manuel ^{[1
,2
]}

Talar-Wojnarowska, Renata ^{[3
]}

Kupcinskas, Juozas ^{[4
]}

Malecka-Panas, Ewa ^{[3
]}

Neoptolemos, John P. ^{[5
]}

Niesen, Willem ^{[6
]}

Vodicka, Pavel ^{[7
,8
]}

Delle Fave, Gianfranco ^{[9
]}

Bueno-de-Mesquita, H. Bas ^{[10
,11
,12
]}

Gazouli, Maria ^{[13
]}

Pacetti, Paola ^{[14
]}

Di Leo, Milena ^{[15
]}

Ito, Hidemi ^{[16
]}

Klueter, Harald ^{[17
]}

Soucek, Pavel ^{[18
,19
]}

Corbo, Vincenzo ^{[20
,21
]}

Yamao, Kenji ^{[22
]}

Hosono, Satoyo ^{[16
]}

Kaaks, Rudolf ^{[23
]}

Vashist, Yogesh ^{[24
]}

Gioffreda, Domenica ^{[25
]}

Strobel, Oliver ^{[6
]}

Shimizu, Yasuhiro ^{[26
]}

Dijk, Frederike ^{[27
]}

Andriulli, Angelo ^{[25
]}

Ivanauskas, Audrius ^{[4
]}

Bugert, Peter ^{[17
]}

Tavano, Francesca ^{[25
]}

Vodickova, Ludmila ^{[8
,28
]}

Zambon, Carlo Federico ^{[29
]}

Lovecek, Martin ^{[30
,31
]}

Landi, Stefano ^{[1
]}

Key, Timothy J. ^{[32
]}

Boggi, Ugo ^{[33
]}

Pezzilli, Raffaele ^{[34
]}

Jamroziak, Krzysztof ^{[35
]}

Mohelnikova-Duchonova, Beatrice ^{[18
,31
,36
]}

Mambrini, Andrea ^{[14
]}

Bambi, Franco ^{[37
]}

Busch, Olivier ^{[38
]}

Pazienza, Valerio ^{[25
]}

Valente, Roberto ^{[9
]}

Theodoropoulos, George E. ^{[39
]}

Hackert, Thilo ^{[6
]}

Capurso, Gabriele ^{[9
]}

Cavestro, Giulia Martina ^{[15
]}

Pasquali, Claudio ^{[40
]}

Basso, Daniela ^{[41
]}

机构：

[1] Univ Pisa, Dept Biol, Pisa, Italy

[2] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany

[3] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland

[4] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania

[5] Univ Liverpool, Inst Hlth Res, Liverpool Pancreas Biomed Res Unit, Liverpool, Merseyside, England

[6] Univ Heidelberg Hosp, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany

[7] Czech Acad Sci, Inst Expt Med, Prague, Czech Republic

[8] Charles Univ Prague, Fac Med 1, Inst Biol & Med Genet, Prague, Czech Republic

[9] Sapienza Univ Rome, S Andrea Hosp, Digest & Liver Dis Unit, Rome, Italy

[10] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands

[11] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[12] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia

[13] Natl & Kapodistrian Univ Athens, Sch Med, Biol Lab, Dept Basic Med Sci, Athens, Greece

[14] Massa Carrara Azienda USL Toscana Nord Ovest, Dept Oncol, Carrara, Italy

[15] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst Milan, Gastroenterol & Gastrointestinal Endoscopy Unit, Milan, Italy

[16] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan

[17] Heidelberg Univ, Med Fac Mannheim, German Red Cross Blood Serv Baden Wurttemberg Hes, Inst Transfus Med & Immunol, Mannheim, Germany

[18] Natl Inst Publ Hlth, Lab Toxicogen, Prague, Czech Republic

[19] Charles Univ Prague, Fac Med Pilsen, Biomed Ctr, Lab Pharmacogen, Plzen, Czech Republic

[20] Univ & Hosp Trust Verona, ARC Net Res Ctr, Verona, Italy

[21] Univ & Hosp Trust Verona, Dept Diagnost & Publ Hlth, Verona, Italy

[22] Aichi Canc Ctr Hosp, Dept Gastroenterol, Nagoya, Aichi, Japan

[23] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[24] Univ Med Ctr Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany

[25] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Soffe, Div Gastroenterol & Res Lab, San Giovanni Rotondo, Italy

[26] Aichi Canc Ctr Hosp, Dept Gastroenterol Surg, Nagoya, Aichi, Japan

[27] Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands

[28] Charles Univ Prague, Fac Med Pilsen, Biomed Ctr, Prague, Czech Republic

[29] Univ Padua, Dept Med DIMED, I-35100 Padua, Italy

[30] Palacky Univ Olomouc, Fac Med & Dent, Dept Surg 1, Olomouc, Czech Republic

[31] Univ Hosp Olomouc, Olomouc, Czech Republic

[32] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Unit, Oxford, England

[33] Pisa Univ Hosp, Div Gen & Transplant Surg, Pisa, Italy

[34] Dant Orsola Malpighi Hosp, Dept Digest Syst, Pancreas Unit, Bologna, Italy

[35] Inst Hematol & Transfus Med, Dept Hematol, Warsaw, Poland

[36] Palacky Univ Olomouc, Fac Med & Dent, Dept Oncol, Olomouc, Czech Republic

[37] Azienda Osped Univ Meyer, Blood Transfus Serv, Florence, Italy

[38] Acad Med Ctr, Dept Surg, Amsterdam, Netherlands

[39] Natl & Kapodistrian Univ Athens, Athens Med Sch, Dept Propaedeut Surg 1, Colorectal Unit, Athens, Greece

[40] Univ Padua, Dept Surg Oncol & Gastroenterol DiSCOG, I-35100 Padua, Italy

[41] Univ Hosp Padova, Dept Lab Med, Padua, Italy

[42] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi, Japan

[43] Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, Clin Gerontol Unit, Box 251, Cambridge, England

[44] Copernicus Mem Hosp, Lab Clin Transplant Immunol & Genet, Lodz, Poland

[45] Univ Pisa, Dept Translat Res & New Technol Med & Surg, Pisa, Italy

来源：

ONCOTARGET | 2016年 / 7卷 / 35期

基金：

美国国家卫生研究院;

关键词：

pancreatic cancer; CDKN2A; single nucleotide polymorphisms; miRSNP; association study; GENOME-WIDE ASSOCIATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; SUSCEPTIBILITY LOCI; REGULATORY MOTIF; VARIANTS; METAANALYSIS; BREAST; GENES; POPULATIONS; FAMILIES;

D O I：

10.18632/oncotarget.10935

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：57011 / 57020

页数：10

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← 1 2 3 4 5 →

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[1] A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer
Al Olama, Ali Amin
Kote-Jarai, Zsofia
Berndt, Sonja I.
Conti, David V.
Schumacher, Fredrick
Han, Ying
Benlloch, Sara
Hazelett, Dennis J.
Wang, Zhaoming
Saunders, Ed
Leongamornlert, Daniel
Lindstrom, Sara
Jugurnauth-Little, Sara
Dadaev, Tokhir
Tymrakiewicz, Malgorzata
Stram, Daniel O.
Rand, Kristin
Wan, Peggy
Stram, Alex
Sheng, Xin
Pooler, Loreall C.
Park, Karen
Xia, Lucy
Tyrer, Jonathan
Kolonel, Laurence N.
Le Marchand, Loic
Hoover, Robert N.
Machiela, Mitchell J.
Yeager, Merideth
Burdette, Laurie
Chung, Charles C.
Hutchinson, Amy
Yu, Kai
Goh, Chee
Ahmed, Mahbubl
Govindasami, Koveela
Guy, Michelle
Tammela, Teuvo L. J.
Auvinen, Anssi
Wahlfors, Tlina
Schleutker, Johanna
Visakorpi, Tapio
Leinonen, Katri A.
Xu, Jianfeng
Aly, Markus
Donovan, Jenny
Travis, Ruth C.
Key, Tim J.
Siddiq, Afshan
Canzian, Federico
[J]. NATURE GENETICS, 2014, 46 (10) : 1103 - 1109
[2] Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer
Amundadottir, Laufey
Kraft, Peter
Stolzenberg-Solomon, Rachael Z.
Fuchs, Charles S.
Petersen, Gloria M.
Arslan, Alan A.
Bueno-de-Mesquita, H. Bas
Gross, Myron
Helzlsouer, Kathy
Jacobs, Eric J.
LaCroix, Andrea
Zheng, Wei
Albanes, Demetrius
Bamlet, William
Berg, Christine D.
Berrino, Franco
Bingham, Sheila
Buring, Julie E.
Bracci, Paige M.
Canzian, Federico
Clavel-Chapelon, Francoise
Clipp, Sandra
Cotterchio, Michelle
de Andrade, Mariza
Duell, Eric J.
Fox, John W., Jr.
Gallinger, Steven
Gaziano, J. Michael
Giovannucci, Edward L.
Goggins, Michael
Gonzalez, Carlos A.
Hallmans, Goran
Hankinson, Susan E.
Hassan, Manal
Holly, Elizabeth A.
Hunter, David J.
Hutchinson, Amy
Jackson, Rebecca
Jacobs, Kevin B.
Jenab, Mazda
Kaaks, Rudolf
Klein, Alison P.
Kooperberg, Charles
Kurtz, Robert C.
Li, Donghui
Lynch, Shannon M.
Mandelson, Margaret
McWilliams, Robert R.
Mendelsohn, Julie B.
Michaud, Dominique S.
[J]. NATURE GENETICS, 2009, 41 (09) : 986 - U47
[3] [Anonymous], HUM GENET
[4] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
Ardlie, Kristin G.
DeLuca, David S.
Segre, Ayellet V.
Sullivan, Timothy J.
Young, Taylor R.
Gelfand, Ellen T.
Trowbridge, Casandra A.
Maller, Julian B.
Tukiainen, Taru
Lek, Monkol
Ward, Lucas D.
Kheradpour, Pouya
Iriarte, Benjamin
Meng, Yan
Palmer, Cameron D.
Esko, Tonu
Winckler, Wendy
Hirschhorn, Joel N.
Kellis, Manolis
MacArthur, Daniel G.
Getz, Gad
Shabalin, Andrey A.
Li, Gen
Zhou, Yi-Hui
Nobel, Andrew B.
Rusyn, Ivan
Wright, Fred A.
Lappalainen, Tuuli
Ferreira, Pedro G.
Ongen, Halit
Rivas, Manuel A.
Battle, Alexis
Mostafavi, Sara
Monlong, Jean
Sammeth, Michael
Mele, Marta
Reverter, Ferran
Goldmann, Jakob M.
Koller, Daphne
Guigo, Roderic
McCarthy, Mark I.
Dermitzakis, Emmanouil T.
Gamazon, Eric R.
Im, Hae Kyung
Konkashbaev, Anuar
Nicolae, Dan L.
Cox, Nancy J.
Flutre, Timothee
Wen, Xiaoquan
Stephens, Matthew
[J]. SCIENCE, 2015, 348 (6235) : 648 - 660
[5] Post-G WAS gene-environment interplay in breast cancer: results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79 000 women
Barrdahl, Myrto
Canzian, Federico
Joshi, Amit D.
Travis, Ruth C.
Chang-Claude, Jenny
Auer, Paul L.
Gapstur, Susan M.
Gaudet, Mia
Diver, W. Ryan
Henderson, Brian E.
Haiman, Christopher A.
Schumacher, Fredrick R.
Le Marchand, Loic
Berg, Christine D.
Chanock, Stephen J.
Hoover, Robert N.
Rudolph, Anja
Ziegler, Regina G.
Giles, Graham G.
Baglietto, Laura
Severi, Gianluca
Hankinson, Susan E.
Lindstroem, Sara
Willet, Walter
Hunter, David J.
Buring, Julie E.
Lee, I-Min
Zhang, Shumin
Dossus, Laure
Cox, David G.
Khaw, Kay-Tee
Lund, Eiliv
Naccarati, Alessio
Peeters, Petra H.
Ramon Quiros, J.
Riboli, Elio
Sund, Malin
Trichopoulos, Dimitrios
Prentice, Ross L.
Kraft, Peter
Kaaks, Rudolf
Campa, Daniele
[J]. HUMAN MOLECULAR GENETICS, 2014, 23 (19) : 5260 - 5270
[6] Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Biankin, Andrew V.
Waddell, Nicola
Kassahn, Karin S.
Gingras, Marie-Claude
Muthuswamy, Lakshmi B.
Johns, Amber L.
Miller, David K.
Wilson, Peter J.
Patch, Ann-Marie
Wu, Jianmin
Chang, David K.
Cowley, Mark J.
Gardiner, Brooke B.
Song, Sarah
Harliwong, Ivon
Idrisoglu, Senel
Nourse, Craig
Nourbakhsh, Ehsan
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