Functional variable number of tandem repeats variation in the promoter of proto-oncogene PTTG1IP is associated with risk of estrogen receptor-positive breast cancer
Functional variable number of tandem repeats variation in the promoter of proto-oncogene PTTG1IP is associated with risk of estrogen receptor-positive breast cancer
复制标题
原癌基因 PTTG1IP 启动子中串联重复序列数量的功能性变异与雌激素受体阳性乳腺癌的风险相关。
DOI：
10.1111/j.1349-7006.2012.02266.x
复制
发表时间：
2012-06-01
期刊：
影响因子：
5.7
通讯作者：
Wang, Haijian
中科院分区：
文献类型：
--
作者：
Xiang, Chan;Gao, Haidong;Wang, Haijian
雌激素受体（ER）信号通路中的遗传多态性可改变乳腺癌的风险。PTTG1IP是内分泌肿瘤中雌激素受体α（ER α）靶向的垂体肿瘤转化基因结合因子，PTTG1IP启动子中的可变数目串联重复序列（VNTR）多态性已被证明是功能性的，但其与癌症病因的相关性尚不清楚。我们通过对658名患者和866名对照进行基因分型，研究了其与乳腺癌风险的相关性，并进一步分析了其与ER α的差异相互作用。我们发现了9种等位基因，范围从2到9和11个重复，形成29个不同的基因型和11个不同的双等位基因重复数。携带6个重复等位基因（比值比[OR]，1.45; 95%置信区间[CI]，1.171.79）、长等位基因（≥ 6个重复）（OR，1.55; 95% CI，1.172.05）或高剂量双等位基因重复（OR，1.38; 95% CI，1.071.77）的受试者患癌症的风险显著增加。在分层分析中，这些关联在ER阳性乳腺癌中一致地表现出来：在ER阳性、PR阳性亚型、具有六个重复等位基因的基因型中（OR，1.42; 95%CI，1.06 ± 1.90），长等位基因（OR，1.77; 95% CI，1.17 - 2.67）或高剂量双等位基因重复序列（OR为1.67; 95% CI为1.192.33）;在ER阳性、HER2阴性亚型中，它们均为易感因素，OR值为1.46（95%CI，1.062.02）、2.06（95%CI，1.283.32）和1.85（95%CI，1.262.71）。此外，功能分析表明，串联重复序列的数量增加增强ER α的结合亲和力。本研究提供了第一个流行病学证据，PTTG1IP的功能调控变体与ER阳性乳腺癌的风险相关，进一步支持其作为乳腺癌原癌基因的相关性。（Cancer Sci 2012; 103：11211128）
Genetic polymorphisms in the signalling pathway of estrogen receptor (ER) could modify the risk of breast cancer. A variable number of tandem repeats (VNTR) polymorphism in the promoter of PTTG1IP, pituitary tumor transforming gene binding factor targeted by estrogen receptor a (ERa) in endocrine neoplasia, has been shown to be functional, but its relevance to cancer etiology was unknown. We investigated its association with breast cancer risk by genotyping in 658 patients and 866 controls and further analysed its differential interaction with ERa. We found nine types of alleles ranging from 2 to 9 and 11 repeats that form 29 distinct genotypes and 11 different biallelic repeat numbers. Subjects who carry the six-repeats allele (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.171.79), long alleles (=6 repeats) (OR, 1.55; 95% CI, 1.172.05) or a high dose of biallelic repeats (OR, 1.38; 95% CI, 1.071.77) were at significantly increased risk of cancer. In stratification analysis, these associations consistently manifested in ER-positive breast cancer: in ER positive, PR-positive subtype, genotypes with the six-repeats allele (OR, 1.42; 95% CI, 1.061.90), long alleles (OR, 1.77; 95% CI, 1.172.67) or a high dose of biallelic repeats (OR, 1.67; 95% CI, 1.192.33) were associated with cancer risk; in ER positive, HER2-negative subtype, they were susceptible factors with the ORs being 1.46 (95% CI, 1.062.02), 2.06 (95% CI, 1.283.32) and 1.85 (95% CI, 1.262.71), respectively. Furthermore, functional analysis revealed that an increase in the number of tandem repeats enhances the binding affinity of ERa. The present study provides the first epidemiological evidence that functional regulatory variants of PTTG1IP were associated with the risk of ER-positive breast cancer, further supporting its relevance as one proto-oncogene in breast cancer. (Cancer Sci 2012; 103: 11211128)