Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

• Keywords
• Association study, Enhancer, Pancreatic cancer, Single nucleotide polymorphism, Transcription factor binding site,
• MeSH
• Genome-Wide Association Study MeSH
• Carcinoma, Pancreatic Ductal * genetics   pathology   MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Pancreatic Neoplasms * genetics   epidemiology   pathology   MeSH
• Regulatory Sequences, Nucleic Acid MeSH
• Transcription Factors genetics   metabolism   MeSH
• Binding Sites genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Transcription Factors MeSH

Pancreatic cancer, a complex disease, emerges as a severe health problem worldwide and it exhibits a poor prognosis and high mortality. Risk factors associated with sporadic pancreatic cancer remain poorly understood, even less is known about disease prognosis due to its rapid progression. The PANcreatic Disease ReseArch (PANDoRA) consortium, of which the authors are members, was established to coordinate the efforts of different research groups to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. PANDoRA consortium has contributed to the identification of several low-penetrance risk loci for the disease both by candidate variants approach and genome-wide association studies, including those in cell-cycle and DNA damage response, telomere homeostasis, SCL and ABC transporters, ABO locus variability, mitochondrial metabolism and it participated on collaborative genome-wide association study approach and implementation of a search for functional-based pancreatic cancer risk loci and long noncoding RNAs. Complex studies covering genetic, environmental and microenvironmental factors in the pancreatic cancer onset, progression and its prognosis are warranted.

• MeSH
• Genome-Wide Association Study MeSH
• Carcinoma, Pancreatic Ductal * genetics   pathology   MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Pancreatic Neoplasms * genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.

• MeSH
• Hyaluronan Receptors genetics   MeSH
• Chitinases genetics   MeSH
• Carcinoma, Pancreatic Ductal genetics   mortality   MeSH
• Polymorphism, Single Nucleotide MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Pancreatic Neoplasms genetics   mortality   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hyaluronan Receptors MeSH
• CD44 protein, human MeSH Browser
• CHI3L2 protein, human MeSH Browser
• Chitinases MeSH
• Biomarkers, Tumor MeSH

ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers. This study investigated significance of protein expression and cellular localization of the previously suggested putative prognostic markers ABCC2 and SLC22A3 in pancreatic cancer patients. Protein localization and brush border staining intensity of ABCC2 and SLC22A3 was assessed in tumor tissue blocks of 65 pancreatic cancer patients and associated with clinical data and survival of patients with regard to therapy. Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient´s death in univariate analyses. Multivariate analyses confirmed the association of SLC22A3 expression with progression-free survival of patients. A subgroup analysis of patients treated with regimens based on nucleoside analogs suggested that patients with negative brush border staining or apical localization of SLC22A3 in tumor cells have worse overall survival. The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival. The present study shows for the first time that the protein presence and to some extent also localization of SLC22A3 significantly associate with prognosis of pancreatic cancer in both unstratified and chemotherapy-treated patients. The combination of ABCC2 and SLC22A3 brush border staining also needs further attention in this regard.

• MeSH
• Adenocarcinoma * metabolism   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Neoplasm Proteins biosynthesis   MeSH
• Pancreatic Neoplasms * metabolism   mortality   pathology   MeSH
• Disease-Free Survival MeSH
• Multidrug Resistance-Associated Protein 2 MeSH
• Organic Cation Transport Proteins biosynthesis   MeSH
• Multidrug Resistance-Associated Proteins biosynthesis   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ABCC2 protein, human MeSH Browser
• Neoplasm Proteins MeSH
• Multidrug Resistance-Associated Protein 2 MeSH
• Organic Cation Transport Proteins MeSH
• Multidrug Resistance-Associated Proteins MeSH
• solute carrier family 22 (organic cation transporter), member 3 MeSH Browser