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

Abstract

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.

ID1 marks the tumorigenesis of pancreatic ductal adenocarcinoma in mouse and human

“…1 E). These genes were also commonly reported to be correlated with tumor development 28 , grading 29 , suppression 30 , 31 , prognosis 32 , tumorigenicity 33 and risk 34 of pancreatic cancer. LincRNA Malat1 promotes aggressive pancreatic cancer proliferation and metastasis via multiple reported signaling pathways 35 – 37 .…”

Keratin 8 Is an Inflammation-Induced and Prognosis-Related Marker for Pancreatic Adenocarcinoma

“…Isoleucine-to-threonine mutation at position 321 was found in some Chinese children who suffered from recurrent pancreatitis [ 45 ]. Pistoni et al combined these findings and pointed out that the reason might be that certain types of gene polymorphisms could promote KRT8 expression [ 18 ]. Our study agreed with the findings above.…”

“…KRT8 was found to participate in lung tissue regeneration and fibrosis after the inflammatory injury [ 17 ]. Gene polymorphism of KRT8 was found in some pancreatitis patients based on a large population-based study [ 18 ]. In murine pancreatitis models, KRT8 was significantly upregulated in pancreas tissue compared with the control group [ 19 ].…”

Developing and validating a survival prediction model based on blood exosomal ceRNA network in patients with PAAD

“…In gastric cancer, high KRT8 expression is illustrated to promote tumor progression and metastasis [ 40 , 41 ]. Pistoni et al [ 42 ] also discovered overexpression of KRT8 in pancreatic cancer and its association with a high risk of developing pancreatic ductal adenocarcinoma. According to studies, KRT19 expression engages adverse tumor differentiation and aggressive behavior in hepatocellular carcinoma [ 43 ].…”