Siegelmann-Danieli N, Buetow K H
Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA.
Br J Cancer. 1999 Feb;79(3-4):456-63. doi: 10.1038/sj.bjc.6690071.
The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat polymorphism at intron 4 of the Cyp19 gene revealed the presence of six common and two rare alleles. Contingency table analysis revealed a significant difference in allelic distribution between cases and controls (chi2 5df = 13.52, P = 0.019). The allele measuring 171 bp was over-represented in cases; of 14 individuals homozygous for this allele, 13 were cases. These individuals had a higher incidence of cancer in family members and an earlier age at diagnosis than other cases. In sequencing Cyp19's coding exons and regulatory regions, we discovered a perfect association between a silent polymorphism (G-->A at Val80) and the high-risk genotype. Our conclusion is that constitutional genetic variation at the Cyp19 locus is associated with the risk of developing breast cancer, with the 171-bp allele serving as the high-risk allele.
芳香化酶可将雄激素转化为雌激素，在调节乳腺中的雌激素水平方面发挥着主要作用，该酶的活性被认为是乳腺癌发生的一个促成因素。我们开展这项研究，旨在评估人类芳香化酶基因（Cyp19）的体质性基因变异在这种疾病发生中的作用。我们对348例乳腺癌患者和145名对照者（均为白种女性）进行基因分型，检测已发表的Cyp19基因第4内含子的四核苷酸重复多态性，结果发现存在6种常见等位基因和2种罕见等位基因。列联表分析显示，病例组和对照组的等位基因分布存在显著差异（χ²5df = 13.52，P = 0.019）。长度为171 bp的等位基因在病例组中过度表达；在14名该等位基因纯合子个体中，有13例为病例。这些个体的家庭成员患癌几率更高，诊断时的年龄也比其他病例更早。在对Cyp19的编码外显子和调控区域进行测序时，我们发现一个沉默多态性（Val80处的G→A）与高危基因型之间存在完美关联。我们的结论是，Cyp19基因座的体质性基因变异与患乳腺癌的风险相关，171-bp等位基因为高危等位基因。
