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Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma
L. Pistoni, M. Gentiluomo, Y. Lu, E. López de Maturana, V. Hlavac, G. Vanella, E. Darvasi, AC. Milanetto, M. Oliverius, Y. Vashist, M. Di Leo, B. Mohelnikova-Duchonova, R. Talar-Wojnarowska, C. Gheorghe, MC. Petrone, O. Strobel, PG. Arcidiacono,...
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Fondazione Tizzi
Fondazione Arpa
12182
Associazione Italiana Ricerca Cancro
UNCE/MED/006
Fondazione Italiana Malattie Pancreas - Ministero Salute
Fondo de Investigaciones Sanitarias
PI0902102
Instituto de Salud Carlos III
IG 17177
AIRC
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
Medline Complete (EBSCOhost)
from 1996-01-01 to 1 year ago
- MeSH
- Alleles MeSH
- Genome-Wide Association Study * MeSH
- Carcinoma, Pancreatic Ductal genetics MeSH
- Genetic Predisposition to Disease * MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Quantitative Trait Loci * MeSH
- Pancreatic Neoplasms genetics MeSH
- GTPase-Activating Proteins genetics MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
1st Department of Medicine University of Szeged Szeged Hungary
ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Department of Biology University of Pisa Pisa Italy
Department of Digestive Tract Diseases Medical University of Łodz Łodz Poland
Department of General Surgery University of Heidelberg Heidelberg Germany
Department of Laboratory Medicine University Hospital of Padova Padua Italy
Department of Surgery Oncology and Gastroenterology DiSCOG University of Padova Padua Italy
Department of Surgery The Pancreas Institute University and Hospital Trust of Verona Verona Italy
Digestive Endoscopy Unit Division of Gastroenterology Humanitas Research Hospital Milan Italy
Division of Gastroenterology San Carlo Hospital Potenza Italy
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Fundeni Clinical Institute Bucharest Romania
Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre Madrid Spain
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Translational Medicine Medical School University of Pécs Pécs Hungary
Institute of Biology and Medical Genetics 1st Medical Faculty Prague Czech Republic
Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic
Sant'Andrea Hospital Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy
Szent György University Teaching Hospital of Fejér County Székesfehérvár Hungary
Unità Operativa Chirurgia Generale e dei Trapianti University of Pisa Pisa Italy
References provided by Crossref.org
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- $a Pistoni, Laura $u Department of Biology, University of Pisa, Pisa, Italy
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- $a Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma / $c L. Pistoni, M. Gentiluomo, Y. Lu, E. López de Maturana, V. Hlavac, G. Vanella, E. Darvasi, AC. Milanetto, M. Oliverius, Y. Vashist, M. Di Leo, B. Mohelnikova-Duchonova, R. Talar-Wojnarowska, C. Gheorghe, MC. Petrone, O. Strobel, PG. Arcidiacono, L. Vodickova, A. Szentesi, G. Capurso, L. Gajdán, G. Malleo, GE. Theodoropoulos, D. Basso, P. Soucek, H. Brenner, RT. Lawlor, L. Morelli, A. Ivanauskas, PanGenEU Study Investigators, EF. Kauffmann, A. Macauda, M. Gazouli, L. Archibugi, M. Nentwich, M. Loveček, GM. Cavestro, P. Vodicka, S. Landi, F. Tavano, C. Sperti, T. Hackert, J. Kupcinskas, R. Pezzilli, A. Andriulli, L. Pollina, E. Kreivenaite, D. Gioffreda, K. Jamroziak, P. Hegyi, JR. Izbicki, SGG. Testoni, RA. Zuppardo, D. Bozzato, JP. Neoptolemos, N. Malats, F. Canzian, D. Campa
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- $a 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.
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