EMSY基因常见变异与乳腺癌和卵巢癌风险：一项使用HapMap标签单核苷酸多态性的病例对照研究。
Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs.
作者信息
Benusiglio Patrick R, Lesueur Fabienne, Luccarini Craig, McIntosh Joan, Luben Robert N, Smith Paula, Dunning Alison, Easton Douglas F, Ponder Bruce A J, Pharoah Paul D
机构信息
Strangeways Research Laboratory, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK.
出版信息
BMC Cancer. 2005 Jul 19;5:81. doi: 10.1186/1471-2407-5-81.
BACKGROUND
EMSY could be involved in low-level susceptibility to breast and ovarian cancer. Gene amplification is seen in a proportion of breast and ovarian tumours and correlates with poor prognosis in breast cancer patients. Furthermore, the EMSY protein silences a transcription activation domain in BRCA2 exon 3.
METHODS
We used a genetic association study design to determine if common genetic variation (frequency > or = 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional.
RESULTS
HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t > g), rs4245443 (IVS7 g > a), rs2513511 (IVS16 a > g), rs2155220 (3'down c > t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a > g) and rs11600501 (IVS10 c > t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population.
CONCLUSION
We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.
背景
EMSY可能与乳腺癌和卵巢癌的低水平易感性有关。在一部分乳腺癌和卵巢肿瘤中可见基因扩增，且这与乳腺癌患者的不良预后相关。此外，EMSY蛋白可使BRCA2外显子3中的转录激活结构域沉默。
方法
我们采用遗传关联研究设计，以确定EMSY中的常见遗传变异（频率≥5%）是否与英国人群的乳腺癌或卵巢癌风险相关。从HapMap数据库中选择单倍型标签单核苷酸多态性（htSNP），并使用Taqman在两组大型英国白人女性研究样本中进行基因分型（乳腺癌组：n = 2343例病例和2284例对照；卵巢癌组：n = 864例病例和864例对照）。HapMap数据可能不足以全面标记EMSY中的遗传变异。因此，我们用变性高效液相色谱法筛选该基因的启动子和编码序列，以识别其他最可能具有功能的SNP。
结果
关于22个SNP的HapMap数据显示，4个htSNP标记了4种常见单倍型：rs2282611（5'上游t>g）、rs4245443（内含子7 g>a）、rs2513511（内含子16 a>g）、rs2155220（3'下游c>t）。我们未观察到任何基因型或相关单倍型与乳腺癌或卵巢癌风险之间存在关联。其余18个HapMap多态性中的17个（94%）被4个选定的htSNP很好地标记（r2s> 0.8）。通过筛选确定的位于外显子-内含子边界附近的另外两个SNP，rs2508740（内含子9 a>g）和rs11600501（内含子10 c>t）的基因型频率在病例组和对照组中也相似。为了模拟未识别的SNP，我们对HapMap数据进行了留一法交叉验证程序；超过95%的常见遗传变异通过标记多态性得到了很好的体现。因此，我们很可能已经标记了我们人群中存在的任何常见的功能性变异。
结论
在两组大型英国白人女性研究样本中，我们未发现EMSY中的常见遗传变异与乳腺癌或卵巢癌风险之间存在关联。
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