Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

被引：48

作者：

Campa, Daniele ^{[1
]}

Matarazzi, Martina ^{[1
,2
]}

Greenhalf, William ^{[3
]}

Bijlsma, Maarten ^{[4
]}

Saum, Kai-Uwe ^{[5
]}

Pasquali, Claudio ^{[6
]}

van Laarhoven, Hanneke ^{[4
]}

Szentesi, Andrea ^{[7
,8
]}

Federici, Francesca ^{[9
]}

Vodicka, Pavel ^{[10
,11
,12
]}

Funel, Niccola ^{[13
]}

Pezzilli, Raffaele ^{[14
]}

Bueno-de-Mesquita, H. Bas ^{[15
,16
,17
,18
]}

Vodickova, Ludmila ^{[10
,11
,12
]}

Basso, Daniela ^{[19
]}

Obazee, Ofure ^{[2
]}

Hackert, Thilo ^{[20
]}

Soucek, Pavel ^{[12
]}

Cuk, Katarina ^{[5
]}

Kaiser, Joerg ^{[20
]}

Sperti, Cosimo ^{[23
]}

Lovecek, Martin ^{[21
,22
]}

Capurso, Gabriele ^{[24
,25
]}

Mohelnikova-Duchonova, Beatrice ^{[26
]}

Khaw, Kay-Tee ^{[27
]}

Koenig, Anna-Katharina ^{[20
]}

Kupcinskas, Juozas ^{[28
]}

Kaaks, Rudolf ^{[29
]}

Bambi, Franco ^{[30
]}

Archibugi, Livia ^{[24
,25
]}

Mambrini, Andrea ^{[9
]}

Cavestro, Giulia Martina ^{[31
]}

Landi, Stefano ^{[1
]}

Hegyi, Peter ^{[7
,8
,32
]}

Izbicki, Jakob R. ^{[33
]}

Gioffreda, Domenica ^{[34
,35
]}

Zambon, Carlo Federico ^{[23
]}

Tavano, Francesca ^{[34
,35
]}

Talar-Wojnarowska, Renata ^{[36
]}

Jamroziak, Krzysztof ^{[37
]}

Key, Timothy J. ^{[38
]}

Delle Fave, Gianfranco ^{[24
]}

Strobel, Oliver ^{[20
]}

Jonaitis, Laimas ^{[28
]}

Andriulli, Angelo ^{[34
,35
]}

Lawlor, Rita T. ^{[39
]}

Pirozzi, Felice ^{[40
]}

Katzke, Verena ^{[29
]}

Valsuani, Chiara ^{[9
]}

Vashist, Yogesh K. ^{[33
]}

机构：

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

[2] German Canc Res Ctr, Genom Epidemiol Grp, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

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

[4] Acad Med Ctr, Med Oncol, Amsterdam, Netherlands

[5] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[6] Univ Padua, Dept Surg Oncol & Gastroenterol DiSCOG, Pancreat & Digest Endocrine Surg, Padua, Italy

[7] Univ Pecs, Inst Translat Med, Pecs, Hungary

[8] Univ Szeged, Dept Med 1, Szeged, Hungary

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

[10] Acad Sci Czech Republ, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic

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

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

[13] Univ Pisa, Unit Expt Surg Pathol, Dept Surg, Pisa, Italy

[14] St Orsola Malpighi Hosp, Dept Digest Syst, Pancreas Unit, Bologna, Italy

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

[16] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands

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

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

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

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

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

[22] Univ Hosp Olomouc, Olomouc, Czech Republic

[23] Univ Padua, Surg Clin Dept Surg 3, Dept Surg Oncol & Gastroenterol DiSCOG, Padua, Italy

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

[25] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Pancreas Translat & Clin Res Ctr, PancreatoBiliary Endoscopy & EUS Div, Milan, Italy

[26] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Dept Oncol, Olomouc, Czech Republic

[27] Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, Clin Gerontol Unit, Cambridge, England

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

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

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

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

[32] MTA SZTE Momentum Translat Gastroenterol Res Grp, Szeged, Hungary

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

[34] IRCCS Osped Casa Sollievo Sofferenza, Div Gastroenterol, San Giovanni Rotondo, Italy

[35] IRCCS Osped Casa Sollievo Sofferenza, Mol Biol Lab, San Giovanni Rotondo, Italy

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

[37] Inst Hematol & Transfus Med, Warsaw, Poland

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

[39] Univ & Hosp Trust Verona, ARC NET, Verona, Italy

[40] IRCCS Osped Casa Sollievo Sofferenza, Div Abdominal Surg, San Giovanni Rotondo, Italy

[41] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[42] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[43] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

来源：

INTERNATIONAL JOURNAL OF CANCER | 2019年 / 144卷 / 06期

关键词：

pancreatic ductal adenocarcinoma; genetic polymorphisms; lymphocyte telomere length; Mendelian randomization; association; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; POLYMORPHISMS; VARIANTS; DISEASE; LONGER; SURVIVAL; TERT;

D O I：

10.1002/ijc.31928

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 x 10(-10)) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 x 10(-6), p(trend) = 3.27 x 10(-7)). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 x 10(-9) for highest vs. lowest quintile; p = 1.82 x 10(-10) as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

引用

页码：1275 / 1283

页数：9

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