STK15 Polymorphisms and Association with Risk of Invasive Ovarian Cancer

STK15 Polymorphisms and Association with Risk of Invasive Ovarian Cancer

¹Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York; ²Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; ³Translational Oncology Laboratory, Barts and the London Queen Mary's School of Medicine and Dentistry, London, United Kingdom; ⁴Department of Viruses, Hormones, and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; and ⁵Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom

Requests for reprints:
Richard A. DiCioccio, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8059; Fax: 716-845-1698. E-mail: richard.dicioccio{at}roswellpark.org

Abstract

STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5′ and 3′ untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5′ UTR g, and 0.25 and 0.24 for 3′ UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5′ UTR C/G, or 3′ UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.

Footnotes

↵6 Electronic data sources: Locus Link: http://www.ncbi.nlm.nih.gov/LocusLink/; dBSNP: http://www.ncbi.nlm.nih.gov/SNP/; Genbank: http://www.ncbi.nlm.nih.gov/Genbank/.
Grant support: Cancer Research UK grants C490/A3331 and C20/A1639, Roswell Park Alliance, National Cancer Institute grant CA71966 and core grant CA16056, and WellBeing grant 510 (H. Song). The National Cancer Institute maintains the Biopolymer Facility, which assisted in DNA sequencing. B.A.J. Ponder is a Gibb Fellow, D.F. Easton is a Principal Fellow, and P.D.P. Pharoah is a Senior Clinical Research Fellow of Cancer Research UK.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Accepted May 14, 2004.
- Received February 27, 2004.
- Revision received May 3, 2004.