Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203-1738, USA.
J Natl Cancer Inst. 2010 Jul 7;102(13):972-81. doi: 10.1093/jnci/djq170. Epub 2010 May 18.
Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population.
We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided.
Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose-response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, P(trend) = 2.5 x 10(-15)). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population.
A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.
大多数从乳腺癌全基因组关联研究中鉴定出的遗传变异在亚洲女性中尚未得到验证。目前尚无风险评估模型可以结合遗传和临床预测因子来预测该人群的乳腺癌风险。
我们分析了最近的全基因组关联研究中确定的 12 个单核苷酸多态性（SNP），这些 SNP 主要来自欧洲血统的女性，与 3039 例病例患者和 3082 例对照参与者的乳腺癌风险相关，这些参与者参加了上海乳腺癌研究。所有参与者均进行了面对面访谈，以获取有关乳腺癌已知和可疑风险因素的信息。c 统计量是一种衡量区分能力的指标，范围从 0.5（随机分类）到 1.0（完美分类），用于评估遗传和已建立的乳腺癌临床预测因子对新建立的中国女性风险评估模型的贡献。该模型中包含的临床预测因子包括初潮年龄、首次活产年龄、腰臀比、乳腺癌家族史和以前诊断的良性乳腺疾病。通过估计模型预测的高于特定风险阈值的一般人群中乳腺癌患者的比例，可以评估模型在风险分层中的效用。所有统计检验均为双侧检验。
发现 8 个 SNP（rs2046210、rs1219648、rs3817198、rs8051542、rs3803662、rs889312、rs10941679 和 rs13281615），每个 SNP 都反映了一个遗传上独立的位点，与乳腺癌风险相关。观察到乳腺癌风险与遗传风险评分之间存在剂量反应关系，遗传风险评分是这 8 个 SNP 效应的综合衡量指标（遗传风险评分最高五分位组的女性与最低五分位组的比值为 1.85，95%置信区间为 1.58 至 2.18，P（趋势）= 2.5 x 10（-15））。遗传风险评分、腰臀比和以前诊断的良性乳腺疾病是乳腺癌风险的前三个预测因子，每个因子均具有统计学意义（P <.001），有助于建立完整的风险评估模型。经过过度拟合调整后，该模型的 c 统计量为 0.6295，显示出有希望将女性分层为不同的风险组；在风险最高的 30%女性组中，近 50%的乳腺癌患者在一般人群中被诊断出来。
包含遗传标记物和临床预测因子的风险评估模型可能有助于将亚洲女性分类为相关风险组，以实现具有成本效益的筛查和其他预防计划。
