Comings David E, Gade-Andavolu Radhika, Cone Lawrence A, Muhleman Donn, MacMurray James P
Department of Medical Genetics, City of Hope Medical Center, Duarte, California 91010, USA.
Cancer. 2003 May 1;97(9):2160-70. doi: 10.1002/cncr.11340.
Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR).
The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls.
Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9.
These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.
尽管BRCA1和BRCA2基因的鉴定备受关注，但这些基因在所有乳腺癌病例中所占比例不到5%。其余病例为散发性。对一项大型双胞胎研究的重新分析表明，遗传因素可能在散发性乳腺癌和其他癌症中起重要作用。散发性乳腺癌是多基因遗传的。多个基因可能具有累加效应，每个基因占变异的一部分。一个可能影响激素反应性乳腺肿瘤发生发展的因素是乳腺暴露于雌激素的持续时间。因此，乳腺癌的人口统计学风险因素之一是月经初潮年龄早。本研究基于这样的假设，即在人口统计学风险因素中起作用的基因本身可能就是乳腺癌风险基因。作者假设与月经初潮时间及相关风险因素相关的六个基因可能是乳腺癌的候选基因。这些基因分别是瘦素基因（LEP）、瘦素受体基因（LEPR）、儿茶酚-O-甲基转移酶基因（COMT）、多巴胺D2受体基因（DRD2）、雌激素1受体基因（ESR1）和雄激素受体基因（AR）。
作者检查了67例绝经后散发性乳腺癌女性和145例性别及种族匹配的对照。
这些基因中的五个占乳腺癌变异（r²）的显著百分比。计算得到以下r²和P值：LEP：0.073，P≤0.0001；LEPR：0.064，P≤0.0002；COMT：0.073，P≤0.0001；AR：0.040，P≤0.0035；DRD2：0.018，P≤0.05。在多变量回归分析中进行评估时，它们共同占乳腺癌变异的24%（P≤0.0001）。在年龄匹配的病例子集中，这些基因占变异的40%（P≤0.00001）。将各个基因得分相加形成乳腺癌风险评分（BCRS），范围为0至17。当在受试者工作特征图中评估BCRS时，全集的曲线下面积为0.80，年龄匹配集的曲线下面积为0.869。不同BCRS评分的相对乳腺癌风险范围为0.10至11.9。
这些结果证明了一种潜在强大的方法，可用于评估多个乳腺癌风险基因的累加效应，从而对女性散发性乳腺癌风险形成潜在的临床有用评估。
