Genetic determinants of telomere length and risk of pancreatic cancer

TY - JOUR

T1 - Genetic determinants of telomere length and risk of pancreatic cancer

T2 - A PANDoRA study

AU - Campa, Daniele

AU - Matarazzi, Martina

AU - Greenhalf, William

AU - Bijlsma, Maarten

AU - Saum, Kai-Uwe

AU - Pasquali, Claudio

AU - van Laarhoven, Hanneke

AU - Szentesi, Andrea

AU - Federici, Francesca

AU - Vodicka, Pavel

AU - Funel, Niccola

AU - Pezzilli, Raffaele

AU - Bueno-de-Mesquita, H Bas

AU - Vodickova, Ludmila

AU - Basso, Daniela

AU - Obazee, Ofure

AU - Hackert, Thilo

AU - Soucek, Pavel

AU - Cuk, Katarina

AU - Kaiser, Jörg

AU - Sperti, Cosimo

AU - Lovecek, Martin

AU - Capurso, Gabriele

AU - Mohelnikova-Duchonova, Beatrice

AU - Khaw, Kay-Tee

AU - König, Anna-Katharina

AU - Kupcinskas, Juozas

AU - Kaaks, Rudolf

AU - Bambi, Franco

AU - Archibugi, Livia

AU - Mambrini, Andrea

AU - Cavestro, Giulia Martina

AU - Landi, Stefano

AU - Hegyi, Péter

AU - Izbicki, Jakob R

AU - Gioffreda, Domenica

AU - Zambon, Carlo Federico

AU - Tavano, Francesca

AU - Talar-Wojnarowska, Renata

AU - Jamroziak, Krzysztof

AU - Key, Timothy J

AU - Fave, Gianfranco Delle

AU - Strobel, Oliver

AU - Jonaitis, Laimas

AU - Andriulli, Angelo

AU - Lawlor, Rita T

AU - Pirozzi, Felice

AU - Katzke, Verena

AU - Valsuani, Chiara

AU - Vashist, Yogesh K

AU - Brenner, Hermann

AU - Canzian, Federico

N1 - © 2018 UICC.

PY - 2019/3/15

Y1 - 2019/3/15

N2 - 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 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 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.

AB - 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 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 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.

KW - Aged

KW - Carcinoma, Pancreatic Ductal/genetics

KW - Case-Control Studies

KW - Europe

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Lymphocytes/metabolism

KW - Male

KW - Middle Aged

KW - Pancreatic Neoplasms/genetics

KW - Polymorphism, Single Nucleotide

KW - Ribonucleoproteins/genetics

KW - Telomerase/genetics

KW - Telomere/metabolism

KW - Telomere Shortening/genetics

U2 - 10.1002/ijc.31928

DO - 10.1002/ijc.31928

M3 - SCORING: Journal article

C2 - 30325019

VL - 144

SP - 1275

EP - 1283

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 6

ER -