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Article

PubMed

This record comes from PubMed

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

Carcinogenesis. 2021 Aug 19 ; 42 (8) : 1037-1045.

ISSN 1460-2180 | 0143-3334
Source

Language English Country Great Britain, England Media print

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid34216462

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

PubMed 34216462
DOI 10.1093/carcin/bgab057
PII: 6314283
Knihovny.cz E-resources

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
Names of Substances
GTPase-Activating Proteins MeSH
SRGAP1 protein, human MeSH Browser

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

CIBERONC Madrid Spain

Colorectal Unit 1st Department of Propaedeutic Surgery Athens Medical School National and Kapodistrian University of Athens Athens Greece

Department of Basic Medical Sciences Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Department of Biology University of Pisa Pisa Italy

Department of Digestive Tract Diseases Medical University of Łodz Łodz Poland

Department of Gastroenterology and Institute for Digestive Research Lithuanian University of Health Sciences Kaunas Lithuania

Department of General Surgery University of Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Hematology Transplantation and Internal Medicine Medical University of Warsaw Warsaw Poland