Dicioccio Richard A, Song Honglin, Waterfall Christy, Kimura Makoto T, Nagase Hiroki, McGuire Valerie, Hogdall Estrid, Shah Mitul N, Luben Robert N, Easton Douglas F, Jacobs Ian J, Ponder Bruce A J, Whittemore Alice S, Gayther Simon A, Pharoah Paul D P, Kruger-Kjaer Susan
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Epidemiol Biomarkers Prev. 2004 Oct;13(10):1589-94.
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.
STK15是一种假定的致癌基因，编码一种与中心体相关的丝氨酸/苏氨酸激酶，其正常功能是确保有丝分裂期间染色体的准确分离。据报道，STK15在卵巢肿瘤中发生扩增，提示其在卵巢癌病理过程中发挥作用。STK15具有多态性，在进化保守区域有两个单核苷酸替换（449t/a和527g/a），导致氨基酸改变（F31I和V57I）。另外两个意义不明的核苷酸替换（287c/g和1891g/c）分别位于5'和3'非翻译区（UTR）。为了进一步了解STK15在卵巢癌中的作用，我们在英国、美国和丹麦的三项基于人群的卵巢癌病例对照研究中对这些多态性进行基因分型和单倍型分析，共纳入1821例病例和2467例对照，并计算患卵巢癌的风险。英国、美国和丹麦对照组中各个多态性的基因型符合哈迪-温伯格平衡。在合并病例组和合并对照组中，I31的罕见等位基因频率分别为0.23和0.21，I57为0.16和0.17，5'UTR g为0.08和0.07，3'UTR c为0.25和0.24。以F31I的FF纯合子作为对照，在合并组数据中，FI杂合子（比值比，1.18；95%置信区间，1.01 - 1.36）、II纯合子（比值比，1.25；95%置信区间，0.89 - 1.75）和I31等位基因携带者（比值比，1.17；95%置信区间，1.02 - 1.35）患卵巢癌的风险增加。对于V57I、5'UTR C/G或3'UTR G/C，所有基因型的卵巢癌风险相对于各自的常见纯合子VV、cc或gg基本一致。合并组数据的单倍型分析显示有7种单倍型，频率在0.02至0.5之间，其中c - F - V - g最为常见。相对于c - F - V - g，没有一种单倍型特异性风险与1有显著差异。这些结果提示F31I的I31等位基因存在卵巢癌风险的显性遗传模式，且I31等位基因可能是一种低外显率的常见卵巢癌易感等位基因。
