BMC Cancer (Apr 2011)

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

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

DOI
https://doi.org/10.1186/1471-2407-11-119
Journal volume & issue
Vol. 11, no. 1
p. 119

Abstract

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Abstract Background KLK15 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. Results In 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. Conclusions We 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.

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