CYP17基因启动子多态性与40岁以下澳大利亚女性乳腺癌的关系

CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

作者信息

Spurdle A B, Hopper J L, Dite G S, Chen X, Cui J, McCredie M R, Giles G G, Southey M C, Venter D J, Easton D F, Chenevix-Trench G

机构信息

Cancer Unit, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research, and The University of Queensland, Brisbane, Australia.

出版信息

J Natl Cancer Inst. 2000 Oct 18;92(20):1674-81. doi: 10.1093/jnci/92.20.1674.

DOI:10.1093/jnci/92.20.1674

PMID:11036113

Abstract

BACKGROUND

The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer.

METHODS

Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed.

RESULTS

Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years.

CONCLUSIONS

The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.

摘要

背景

细胞色素P450c17α酶在类固醇生物合成途径中发挥作用，据报道，CYP17基因5'启动子区域的T到C多态性与内源性类固醇激素水平改变有关。由于已知类固醇激素暴露会影响乳腺癌风险，我们开展了一项基于人群的病例对照家系研究，以评估CYP17启动子多态性与早发性乳腺癌之间的关系。

方法

对诊断为原发性乳腺癌的40岁以下病例受试者、人群抽样的对照受试者以及病例和对照受试者的亲属进行访谈，记录乳腺癌家族史和其他风险因素。在369例病例受试者、284例对照受试者和91例病例受试者的亲属中确定CYP17基因型。通过逻辑回归比较基因型分布，并通过改良的分离分析估计累积风险。所有统计检验均为双侧检验。

结果

与TT基因型（即T等位基因纯合个体）相比，TC基因型与乳腺癌风险增加无关（P = 0.7）。与TT和TC基因型合并相比，CC基因型在调整测量的风险因素之前的相对风险为1.81（95%置信区间[CI]=1.15 - 2.86；P = 0.01），调整后为1.63（95%CI = 1.00 - 2.64；P = 0.05）。与未按乳腺癌家族史分层的对照受试者相比，至少有一位一级或二级亲属患癌的病例受试者中CC基因型过多（23%对11%；P = 0.006），这些病例受试者的风险比根据基因型和乳腺癌家族史定义的其他组的女性高两到三倍。对CC基因型病例受试者的一级和二级亲属中的乳腺癌进行分析，排除两名已知的BRCA1或BRCA2有害突变携带者，CC基因型女性的相对风险为3.48（95%CI = 1.13 - 10.74；P = 0.04），相当于到70岁时的累积风险为16%。