Pancreatic Cancer Susceptibility Loci and Their Role in Survival

Kay Tee Khaw ,Jörg D. Hoheisel,Afshan Siddiq,Andrea S. Bauer ,Rajiv Kumar,John P. Neoptolemos,Eithne Costello,William Greenhalf,Daniele Campa,Tim Key ,Markus W. Büchler,Jens Werner,Barbara Burwinkel,Justo Lorenzo Bermejo ,Michaela Schanné,Cosmeri Rizzato,Federico Canzian,P. Sivaramakrishna Rachakonda,Nathalia A. Giese

doi:10.1371/journal.pone.0027921

Abstract

Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.

Highlights

Pancreatic cancer is the fifth leading cause of cancer deaths in Europe and the eighth worldwide, with a five year relative survival of less than 5% [1]
The genotype distributions at all loci were in Hardy-Weinberg equilibrium in controls, with non-significant chi square values
In the German population, we found that the heterozygous carriers had a better survival (HR = 0.73, 95%confidence intervals (CI) 0.59–0.91, Pvalue = 0.01, median survival of heterozygotes = 440 days, median survival of homozygotes for the common allele = 346 days), while in the British population a better survival was observed in homozygous carriers of the variant allele (HR = 0.40, 95%CI 0.16–1.01, P = 0.05, median survival of homozygotes for the variant allele = 421 days, median survival of homozygotes for the common allele = 287 days)

Summary

Introduction

Pancreatic cancer is the fifth leading cause of cancer deaths in Europe and the eighth worldwide, with a five year relative survival of less than 5% [1]. Established risk factors include cigarette smoking, obesity or overweight, a medical history of diabetes type II, and family history of pancreatic cancer [2]. The PanScan project, a genome-wide association study (GWAS), recently identified various pancreatic cancer susceptibility loci. Several single nucleotide polymorphisms (SNPs) in the gene regions of ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk [3]. Significant associations were found with SNPs mapping to a region on chromosome 13q22.1 and a region on chromosome 15q14, where no known genes are mapped [3]

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Results

Conclusion