A Kallikrein 15 (KLK15) Single Nucleotide Polymorphism Located Close to a Novel Exon Shows Evidence of Association with Poor Ovarian Cancer Survival

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2011 Apr 5

PMID 21457553

Citations 6

Authors

Jyotsna Batra

Christina M Nagle

Tracy OMara

Melanie Higgins

Ying Dong

Olivia L Tan

Felicity Lose

Lene Marie Skeie

Srilakshmi Srinivasan

Kelly L Bolton

Honglin Song

Susan J Ramus

Simon A Gayther

Paul D P Pharoah

Mary-Anne Kedda

Amanda B Spurdle

Judith A Clements

Affiliations

Soon will be listed here.

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 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.

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.

Citing Articles

Association Analysis of a Microsatellite Repeat in the Gene With Prostate Cancer Risk, Aggressiveness and Survival.

Moya L, Lai J, Hoffman A, Srinivasan S, Panchadsaram J, Chambers S Front Genet. 2018; 9:428.

PMID: 30337939 PMC: 6180282. DOI: 10.3389/fgene.2018.00428.

A microsatellite repeat in PCA3 long non-coding RNA is associated with prostate cancer risk and aggressiveness.

Lai J, Moya L, An J, Hoffman A, Srinivasan S, Panchadsaram J Sci Rep. 2017; 7(1):16862.

PMID: 29203868 PMC: 5715103. DOI: 10.1038/s41598-017-16700-y.

Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes.

Stefanini A, da Cunha B, Henrique T, Tajara E Dis Markers. 2016; 2015:946572.

PMID: 26783378 PMC: 4689925. DOI: 10.1155/2015/946572.

Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer.

Chen X, Paranjape T, Stahlhut C, McVeigh T, Keane F, Nallur S Oncogene. 2014; 34(16):2125-37.

PMID: 24909162 PMC: 4326598. DOI: 10.1038/onc.2014.117.

Candidate gene association studies: a comprehensive guide to useful in silico tools.

Patnala R, Clements J, Batra J BMC Genet. 2013; 14:39.

PMID: 23656885 PMC: 3655892. DOI: 10.1186/1471-2156-14-39.

References

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

Emami N, Diamandis E . Utility of kallikrein-related peptidases (KLKs) as cancer biomarkers. Clin Chem. 2008; 54(10):1600-7. DOI: 10.1373/clinchem.2008.105189. View

Batra J, Tan O, OMara T, Zammit R, Nagle C, Clements J . Kallikrein-related peptidase 10 (KLK10) expression and single nucleotide polymorphisms in ovarian cancer survival. Int J Gynecol Cancer. 2010; 20(4):529-36. DOI: 10.1111/IGC.0b013e3181d9273e. View

Li X, Yan P, Shao Z . Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene. 2009; 28(44):3937-48. DOI: 10.1038/onc.2009.245. View

Olejek A, Damasiewicz-Bodzek A, Bodzek P, Wielkoszynski T, Zamlynski J, Stoltny P . Concentrations of antibodies against heat shock protein 27 in the sera of women with ovarian carcinoma. Int J Gynecol Cancer. 2009; 19(9):1516-20. DOI: 10.1111/IGC.0b013e3181bf425b. View

Kurlender L, Borgono C, Michael I, Obiezu C, Elliott M, Yousef G . A survey of alternative transcripts of human tissue kallikrein genes. Biochim Biophys Acta. 2005; 1755(1):1-14. DOI: 10.1016/j.bbcan.2005.02.001. View

Coughlin S, Hall I . A review of genetic polymorphisms and prostate cancer risk. Ann Epidemiol. 2002; 12(3):182-96. DOI: 10.1016/s1047-2797(01)00310-6. View

Lawrence M, Veveris-Lowe T, Whitbread A, Nicol D, Clements J . Epithelial-mesenchymal transition in prostate cancer and the potential role of kallikrein serine proteases. Cells Tissues Organs. 2007; 185(1-3):111-5. DOI: 10.1159/000101311. View

Yousef G, Diamandis E . An overview of the kallikrein gene families in humans and other species: emerging candidate tumour markers. Clin Biochem. 2003; 36(6):443-52. DOI: 10.1016/s0009-9120(03)00055-9. View

10.

Lose F, Nagle C, OMara T, Batra J, Bolton K, Song H . Vascular endothelial growth factor gene polymorphisms and ovarian cancer survival. Gynecol Oncol. 2010; 119(3):479-83. DOI: 10.1016/j.ygyno.2010.08.014. View

11.

Clements J . Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?. Biol Chem. 2008; 389(12):1447-54. DOI: 10.1515/BC.2008.174. View

12.

Yousef G, Scorilas A, Jung K, Ashworth L, Diamandis E . Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. J Biol Chem. 2000; 276(1):53-61. DOI: 10.1074/jbc.M005432200. View

13.

Yousef G, Scorilas A, Katsaros D, Fracchioli S, Iskander L, Borgono C . Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J Clin Oncol. 2003; 21(16):3119-26. DOI: 10.1200/JCO.2003.09.111. View

14.

Karni R, de Stanchina E, Lowe S, Sinha R, Mu D, Krainer A . The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007; 14(3):185-93. PMC: 4595851. DOI: 10.1038/nsmb1209. View

15.

Song H, Ramus S, Kjaer S, Dicioccio R, Chenevix-Trench G, Pearce C . Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study. Hum Mol Genet. 2009; 18(12):2297-304. PMC: 2685754. DOI: 10.1093/hmg/ddp138. View

16.

Laskowska E, Matuszewska E, Kuczynska-Wisnik D . Small heat shock proteins and protein-misfolding diseases. Curr Pharm Biotechnol. 2010; 11(2):146-57. DOI: 10.2174/138920110790909669. View

17.

Whitbread A, Veveris-Lowe T, Dong Y, Tan O, Gardiner R, Samaratunga H . Expression of PSA-RP2, an alternatively spliced variant from the PSA gene, is increased in prostate cancer tissues but the protein is not secreted from prostate cancer cells. Biol Chem. 2010; 391(4):461-6. DOI: 10.1515/BC.2010.043. View

18.

Brookfield K, Cheung M, Koniaris L, Sola J, Fischer A . A population-based analysis of 1037 malignant ovarian tumors in the pediatric population. J Surg Res. 2009; 156(1):45-9. DOI: 10.1016/j.jss.2009.03.069. View

19.

Fischer D, Noack K, Runnebaum I, Watermann D, Kieback D, Stamm S . Expression of splicing factors in human ovarian cancer. Oncol Rep. 2004; 11(5):1085-90. View

20.

Mavridis K, Avgeris M, Koutalellis G, Stravodimos K, Scorilas A . Expression analysis and study of the KLK15 mRNA splice variants in prostate cancer and benign prostatic hyperplasia. Cancer Sci. 2010; 101(3):693-9. PMC: 11158190. DOI: 10.1111/j.1349-7006.2009.01450.x. View