TY  - JOUR
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
TI  - Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.
JO  - Carcinogenesis
VL  - 42
IS  - 8
SN  - 1460-2180
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2021-01513
SP  - 1037–1045
PY  - 2021
N1  -  Volume 42, Issue 8, August 2021, Pages 1037–1045
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 tumor cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P=3.56×10 -6). This SNP 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.
KW  - association study (Other)
KW  - eQTLs (Other)
KW  - pancreatic cancer (Other)
KW  - single nucleotide polymorphisms (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34216462
DO  - DOI:10.1093/carcin/bgab057
UR  - https://inrepo02.dkfz.de/record/169706
ER  -