Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

TY - JOUR

T1 - Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

AU - Pistoni, Laura

AU - Gentiluomo, Manuel

AU - Lu, Ye

AU - López de Maturana, Evangelina

AU - Hlavac, Viktor

AU - Vanella, Giuseppe

AU - Darvasi, Erika

AU - Milanetto, Anna Caterina

AU - Oliverius, Martin

AU - Vashist, Yogesh

AU - Di Leo, Milena

AU - Mohelnikova-Duchonova, Beatrice

AU - Talar-Wojnarowska, Renata

AU - Gheorghe, Cristian

AU - Petrone, Maria Chiara

AU - Strobel, Oliver

AU - Arcidiacono, Paolo Giorgio

AU - Vodickova, Ludmila

AU - Szentesi, Andrea

AU - Capurso, Gabriele

AU - Gajdán, László

AU - Malleo, Giuseppe

AU - Theodoropoulos, George E

AU - Basso, Daniela

AU - Soucek, Pavel

AU - Brenner, Hermann

AU - Lawlor, Rita T

AU - Morelli, Luca

AU - Ivanauskas, Audrius

AU - Kauffmann, Emanuele Federico

AU - Macauda, Angelica

AU - Gazouli, Maria

AU - Archibugi, Livia

AU - Nentwich, Michael

AU - Loveček, Martin

AU - Cavestro, Giulia Martina

AU - Vodicka, Pavel

AU - Landi, Stefano

AU - Tavano, Francesca

AU - Sperti, Cosimo

AU - Hackert, Thilo

AU - Kupcinskas, Juozas

AU - Pezzilli, Raffaele

AU - Andriulli, Angelo

AU - Pollina, Luca

AU - Kreivenaite, Edita

AU - Gioffreda, Domenica

AU - Jamroziak, Krzysztof

AU - Hegyi, Péter

AU - Izbicki, Jakob R

AU - Testoni, Sabrina Gloria Giulia

AU - Zuppardo, Raffaella Alessia

AU - Bozzato, Dania

AU - Neoptolemos, John P

AU - Malats, Núria

AU - Canzian, Federico

AU - Campa, Daniele

AU - PanGenEU Study Investigators

N1 - © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2021/8/19

Y1 - 2021/8/19

N2 - Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

AB - Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

U2 - 10.1093/carcin/bgab057

DO - 10.1093/carcin/bgab057

M3 - SCORING: Journal article

C2 - 34216462

VL - 42

SP - 1037

EP - 1045

JO - CARCINOGENESIS

JF - CARCINOGENESIS

SN - 0143-3334

IS - 8

ER -