TY - JOUR
TI - Associations between pancreatic expression quantitative traits and risk
of pancreatic ductal adenocarcinoma
AU - Pistoni, Laura
AU - Gentiluomo, Manuel
AU - Lu, Ye
AU - de Maturana,
AU - Evangelina Lopez
AU - Hlavac, Viktor
AU - Vanella, Giuseppe
AU - Darvasi,
AU - Erika
AU - Milanetto, Anna Caterina
AU - Oliverius, Martin
AU - Vashist,
AU - Yogesh
AU - Di Leo, Milena
AU - Mohelnikova-Duchonova, Beatrice and
AU - Talar-Wojnarowska, Renata
AU - Gheorghe, Cristian
AU - Petrone, Maria
AU - Chiara
AU - Strobel, Oliver
AU - Arcidiacono, Paolo Giorgio
AU - Vodickova,
AU - Ludmila
AU - Szentesi, Andrea
AU - Capurso, Gabriele
AU - Gajdan, Laszlo
AU - and Malleo, Giuseppe
AU - Theodoropoulos, George E.
AU - Basso, Daniela
AU - and Soucek, Pavel
AU - Brenner, Hermann
AU - Lawlor, Rita T.
AU - Morelli,
AU - Luca
AU - Ivanauskas, Audrius
AU - Kauffmann, Emanuele Federico and
AU - Macauda, Angelica
AU - Gazouli, Maria
AU - Archibugi, Livia
AU - Nentwich,
AU - Michael
AU - Cavestro, Giulia Martina
AU - Vodicka, Pavel
AU - Landi,
AU - Stefano
AU - Tavano, Francesca
AU - Sperti, Cosimo
AU - Hackert, Thilo and
AU - Kupcinskas, Juozas
AU - Pezzilli, Raffaele
AU - Andriulli, Angelo and
AU - Pollina, Luca
AU - Kreivenaite, Edita
AU - Gioffreda, Domenica and
AU - Jamroziak, Krzysztof
AU - Hegyi, Peter
AU - Izbicki, Jakob R.
AU - Testoni,
AU - Sabrina Gloria Giulia
AU - Zuppardo, Raffaella Alessia
AU - Bozzato, Dania
AU - and Neoptolemos, John P.
AU - Malats, Nuria
AU - Canzian, Federico and
AU - Campa, Daniele
AU - Lovecek, Martin
JO - Journal of Carcinogenesis
PY - 2021
VL - 42
TODO - 8
SP - 1037-1045
PB - Oxford University Press
SN - 1477-3163
TODO - 10.1093/carcin/bgab057
TODO - null
TODO - 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 x
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 x
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.
ER -