@article{ddd38769512948b9a895b8194cb52a57,
title = "A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival",
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.",
keywords = "Kallikrein 15single nucleotide polymorphismsovarian cancer, splice variants",
author = "Jyotsna Batra and Nagle, {Christina M.} and Tracy O'Mara and Melanie Higgins and Ying Dong and Tan, {Olivia L.} and Felicity Lose and Skeie, {Lene M.} and Srilakshmi Srinivasan and Bolton, {Kelly L.} and Honglin Song and Ramus, {Susan J.} and Gayther, {Simon A.} and Pharoah, {Paul D.P.} and Kedda, {Mary Anne} and Spurdle, {Amanda B.} and Clements, {Judith A.}",
note = "Funding Information: We thank the patients and control subjects who participated so willingly in our studies. For the Australian sample sets, the authors are very grateful to staff at the Australian Red Cross Blood Services for their assistance with the collection of risk factor information and blood samples of healthy donor controls. We thank Georgia Chenevix-Trench for access to DNA samples and associated data for the ovarian cancer and SNP association studies. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre. The results published here are in part based upon data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov. ABS and JAC are NHMRC Senior and Principal Research Fellows respectively. CMN is supported by an NHMRC Career Development Award. JB and OLT are supported by Institute of Health and Biomedical Innovation Postdoctoral Fellowships. TOM is supported by an Australian Postgraduate Award complemented with an IHBI and QLD Government Smart State Postgraduate Awards. SEARCH is funded through a program grant from Cancer Research UK. This work was supported by funding from the National Health and Medical Research Council of Australia (NHMRC) grant 390123.",
year = "2011",
month = apr,
day = "1",
doi = "10.1186/1471-2407-11-119",
language = "English",
volume = "11",
journal = "BMC Cancer",
issn = "1471-2407",
}