Australian Prostate Cancer Research centre-Queensland and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia.
BMC Cancer. 2011 Apr 1;11:119. doi: 10.1186/1471-2407-11-119.
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.
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 15 bp 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.
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.
KLK15 过表达被报道为卵巢癌无进展生存期和总生存期缩短的一个重要预测因子。我们的目的是分析 KLK15 基因中可能存在的功能性单核苷酸多态性（SNP），并评估这些 SNP 以及 KLK15 HapMap 标签 SNP 与卵巢癌生存之间的关联。
通过计算机分析确定 KLK15 调控元件，并对这些区域内的潜在功能性 SNP 进行分类。对卵巢癌细胞系和侵袭性卵巢癌患者的 DNA 测序进行 SNP 验证和鉴定后，选择了 9 个 SNP，并使用Sequenom iPLEX Mass Array 平台在澳大利亚卵巢癌患者队列（N=319）中进行基因分型。在澳大利亚数据集，我们观察到 KLK15 rs266851 SNP 在显性模型中的生存显著恶化（危险比[HR]1.42，95%置信区间[CI]1.02-1.96）。在两个独立数据集的相同方向观察到这种关联，三项研究的合并 HR 为 1.16（1.00-1.34）。该 SNP 位于一个新外显子的 15bp 下游，预测与 mRNA 剪接有关。突变等位基因也预测会破坏 HSF-2 结合位点。
我们提供了 SNP rs266851 与卵巢癌生存相关的证据。我们的结果为下游功能测定和额外的独立验证研究提供了动力，以评估 KLK15 调节 SNP 以及具有替代细胞内功能的 KLK15 同工型在卵巢癌生存中的作用。
