PANcreatic Disease ReseArch Research Articles

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10−15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10−9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10−8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10−8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10−4-2.0×10−3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk.

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Association of Genetic Polymorphisms with Survival in Pancreatic Ductal Adenocarcinoma Patients

Context Overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients is only partially explained by clinical and pathological features. Germline genetic variability can contribute to variation in OS of PDAC patients. A genome-wide association study (GWAS) on PDAC OS has been recently performed. Twenty-eight genomic regions showed association with OS with P<10 -5 . Objective We sought to confirm the reported associations of single nucleotide polymorphisms (SNPs) with OS of PDAC in the PANcreatic Disease ReseArch (PANDoRA) consortium. Methods We genotyped 41 SNPs tagging the 28 regions emerging from the GWAS in up to 1,236 PDAC cases of Caucasian origin from the PANDoRA consortium. We tested each SNP for association with OS of the patients. Results We observed statistically significant associations with OS of PDAC patients at three regions, located in the CTNNA2 gene on chromosome 2 (rs1567532; HR=1.58, 95% CI: 1.24-2.01; P=2.4x10 -4 ), in the ASTN2 gene on chromosome 9 (rs10818020; HR=0.74, 95% CI: 0.61-0.91, P=4x10 -3 ), and in the SMAP2 gene on chromosome 1 (rs16827275; HR=1.61, 95% CI: 1.00-2.60; P=0.049). Among three SNPs reported by the previous GWAS to be associated with OS with P<10 -6 , we observed a weak association at rs16861827 on chromosome 1 (HR=1.69, 95% CI: 1.02-2.80; P=0.043), but did not confirm the other two. All associations were observed with a recessive model. Conclusion These findings add to the evidence that germline genetic polymorphisms affect OS of PDAC patients. If confirmed in further studies, these variants may have the potential to impact treatment decisions and design of clinical trials.

Gaps and Opportunities in Pancreatic Disease Research

Gaps and Opportunities in Pancreatic Disease Research

ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium.

There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or Ballele in comparison with the Oallele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.

Lack of Replication of Seven Pancreatic Cancer Susceptibility Loci Identified in Two Asian Populations

Two recent genome-wide association studies (GWAS) of pancreatic ductal adenocarcinoma (PDAC), conducted, respectively, in a Japanese and in a Chinese population, identified eight novel loci affecting PDAC risk. We attempted to replicate the novel loci in a series of PDACs and healthy controls of European ancestry in the context of the newly formed PANcreatic Disease ReseArch (PANDoRA) consortium. We genotyped seven single-nucleotide polymorphisms (SNP): rs12413624, rs1547374, rs372883, rs5768709, rs6464375, rs708224, rs9502893 (one SNP identified in the Chinese GWAS is not polymorphic in Caucasians) in 1,299 PDAC cases and 2,884 controls. We also attempted stratified analysis considering the different stages of the disease and addressed the possible involvement of the selected SNPs on the survival of patients. None of the SNPs were significantly associated with PDAC risk if considering the overall population of the consortium. When stratifying for country of origin, we found that in the Polish subgroup, the G allele of rs372883 was statistically significantly associated with increased risk [OR, 6.40; 95% confidence interval (CI), 2.28-17.91]. However, the sample size of the subgroups was rather small; therefore, this result can be due to chance. None of the SNPs was associated with disease progression or survival. None of the SNPs associated with PDAC risk in two Asian populations were convincingly associated with PDAC risk in individuals of European descent. This study illustrates the importance of evaluation of PDAC risk markers across ethnic groups.

Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.

Genetic susceptibility to pancreatic cancer and its functional characterization: The PANcreatic Disease ReseArch (PANDoRA) consortium

Genetic susceptibility to pancreatic cancer and its functional characterization: The PANcreatic Disease ReseArch (PANDoRA) consortium

Genetic susceptibility to pancreatic cancer and its functional characterization: The PANcreatic Disease ReseArch (PANDoRA) consortium

Genetic susceptibility to pancreatic cancer and its functional characterization: The PANcreatic Disease ReseArch (PANDoRA) consortium

Gene-Wide Association Study on the TERT Locus and PDAC Susceptibility. Results from the PANDoRA Consortium

Context SNPs in the telomerase reverse transcriptase ( TERT ) locus were reported to be associated with pancreatic cancer risk in a genome-wide association study (GWAS). TERT is essential for maintaining telomere ends. Its over-expression in normal cells can lead to prolonged cell lifespan and transformation. While telomerase activity cannot be detected in most normal tissues, it is seen in approximately 90% of human cancers. Objective We attempted to replicate and expand the association with the locus in a series of PDAC and healthy controls of European ancestry within the PANcreatic Disease ReseArch (PANDoRA) consortium. Methods We genotyped 13 SNPs in 1,034 PDAC cases and 2,443 controls from the PANDoRA consortium. We tested each SNP for association with PDAC risk and also with survival of the patients. Results We replicated the association reported in the GWAS with rs401681 (OR=1.53; 95%C;I 1.22-1.92; P=0.0002) and found a novel association between rs2736098 and decreased PDAC risk (OR=0.75; 95%CI: 0.63-0.88; P=0.001). Another polymorphism (rs4246742) was associated with worse survival (HR=1.75, 95%CI: 1.15-2.67; P=0.009). Conclusion We report here two novel findings: an association with risk (rs2736098) and one with survival of the patients (rs4246742). These results further contribute to our understanding in the genetic etiology of pancreatic cancer and suggest a new marker for disease prognosis.

Variant AB0 Blood Group Alleles and Risk of Pancreatic Cancer: Results from the PANDoRA Consortium

Context Several early studies reported an association between AB0 blood type and pancreatic cancer risk. A genome-wide association study (GWAS) recently reported association between SNPs at the AB0 locus and pancreatic cancer risk. Objective We attempted to replicate and expand the association with the locus in a series of PDAC and healthy controls of European ancestry within the PANcreatic Disease ReseArch (PANDoRA) consortium. Methods We genotyped 6 functional SNPs enabling the prediction the AB0 blood groups in 1,028 PDAC cases and 2,252 controls from the PANDoRA consortium. We tested each SNP and the predicted blood type for association with PDAC risk and also assessed whether the risk SNPs and blood types have an impact on survival of the patients. Results We replicated the association reported in the GWAS with rs505922 (OR=1.18; 95% CI: 1.001-1.39; P=0.048). We also confirmed the associations with blood group A (OR=1.24: 95% CI: 1.04-1.48; P=0.015), and in particular with subgroup A1. We do not find association with blood groups B and AB. We did not find any statistically significant association between SNPs in AB0 or blood group and survival or different staging of cancer. Conclusion AB0 alleles corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk.