A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival

Jyotsna Batra,Ying Dong,Olivia L Tan,Simon A Gayther,Christina M Nagle,Honglin Song,Susan J Ramus,Mary-Anne Kedda,Paul Dp Pharoah,Felicity Lose,Lene Marie Skeie,Melanie Higgins,Srilakshmi Srinivasan,Kelly L Bolton,Amanda B Spurdle,Judith A Clements,Tracy O'Mara

doi:10.1186/1471-2407-11-119

Abstract

BackgroundKLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival.ResultsIn silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site.ConclusionsWe provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.

Highlights

KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer
We have recently identified a PSA promoter single nucleotide polymorphisms (SNPs) to be associated with ovarian cancer survival (O’Mara, manuscript submitted), no studies have been undertaken to assess the role of KLK15 genetic variation in ovarian cancer prognosis
We used in silico approaches for data mining of the KLK15 gene for potential functional motifs and differential splicing to determine regions of the gene that could be functionally compromised by genetic variations

Summary

Introduction

KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. We have recently identified a PSA promoter SNP to be associated with ovarian cancer survival (O’Mara, manuscript submitted), no studies have been undertaken to assess the role of KLK15 genetic variation in ovarian cancer prognosis. We used in silico approaches for data mining of the KLK15 gene for potential functional motifs and differential splicing to determine regions of the gene that could be functionally compromised by genetic variations. This was supplemented by identification of potentially functional common SNPs using database searches and resequencing of ovarian cancer cell lines and patients, to prioritize variants for ovarian cancer prognosis studies. We assessed the association between ovarian cancer survival and 9 SNPs tagging 22 prioritized KLK15 SNPs in an Australian dataset, and undertook replication studies in two other ovarian cancer studies to validate our findings

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