Περίληψη:
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.
Συγγραφείς:
Pistoni, Laura
Gentiluomo, Manuel
Lu, Ye
de Maturana,
Evangelina Lopez
Hlavac, Viktor
Vanella, Giuseppe
Darvasi,
Erika
Milanetto, Anna Caterina
Oliverius, Martin
Vashist,
Yogesh
Di Leo, Milena
Mohelnikova-Duchonova, Beatrice and
Talar-Wojnarowska, Renata
Gheorghe, Cristian
Petrone, Maria
Chiara
Strobel, Oliver
Arcidiacono, Paolo Giorgio
Vodickova,
Ludmila
Szentesi, Andrea
Capurso, Gabriele
Gajdan, Laszlo
and Malleo, Giuseppe
Theodoropoulos, George E.
Basso, Daniela
and Soucek, Pavel
Brenner, Hermann
Lawlor, Rita T.
Morelli,
Luca
Ivanauskas, Audrius
Kauffmann, Emanuele Federico and
Macauda, Angelica
Gazouli, Maria
Archibugi, Livia
Nentwich,
Michael
Cavestro, Giulia Martina
Vodicka, Pavel
Landi,
Stefano
Tavano, Francesca
Sperti, Cosimo
Hackert, Thilo and
Kupcinskas, Juozas
Pezzilli, Raffaele
Andriulli, Angelo and
Pollina, Luca
Kreivenaite, Edita
Gioffreda, Domenica and
Jamroziak, Krzysztof
Hegyi, Peter
Izbicki, Jakob R.
Testoni,
Sabrina Gloria Giulia
Zuppardo, Raffaella Alessia
Bozzato, Dania
and Neoptolemos, John P.
Malats, Nuria
Canzian, Federico and
Campa, Daniele
Lovecek, Martin
