ORAL CONTRACEPTIVES, HORMONAL RISK FACTORS AND BRCA1

描述（申请人描述）：乳腺癌易感基因BRCA1的突变可能与大量早期诊断的乳腺癌有关。然而，乳腺癌发生的年龄似乎有很大的不同，即使是来自同一家族的具有相同突变的女性。此外，最近的证据表明，BRCA1突变携带者患乳腺癌的风险远低于之前报道的85%。这表明，其他遗传或非遗传因素在携带BRCA1突变的女性是否或何时发生乳腺癌方面发挥了作用。流行病学证据表明，早期使用口服避孕药可能会增加患乳腺癌的风险。此外，对于有家族病史的年轻女性来说，口服避孕药的使用似乎尤其有害。我们有初步的数据表明，BRCA1突变携带者比非携带者有更高的使用卵巢癌的风险。在BRCA1突变携带者中使用OC的这种有害影响可能是由于这些女性的乳腺细胞增殖增加。实验证据表明BRCA1可能是激素诱导的负生长调节剂。我们建议开展一项基于人群的研究，以确定BRCA1突变携带者与使用OC相关的乳腺癌相对危险度与非携带者使用OC相关的乳腺癌相对危险度之比。这些信息随后可用于确定BRCA1突变携带者使用OC相关的乳腺癌相对风险。本研究的次要目的是确定BRCA1突变携带者和非携带者中其他激素风险因素（如选择的生殖因素和体育锻炼）对乳腺癌风险的影响是否存在差异。这项研究将为BRCA1在乳腺癌病因学中的作用提供有价值的流行病学信息，并可能在制定BRCA1突变妇女的干预方案和适当咨询方面产生重要结果。

DESCRIPTION (Applicant's Description): Mutations in the breast cancer susceptibility gene BRCA1 may be involved in a substantial number of breast cancers diagnosed at an early age. However, the age at which breast cancer occurs appears to vary substantially, even in women from the same family with the same mutation. Further, recent evidence suggests that breast cancer risk in BRCA1 mutation carriers is much lower than the previously reported 85%. This suggests that other, genetic or nongenetic, factors play a role in whether or when breast cancer occurs in women with a BRCA1 mutation. Epidemiological evidence suggests that oral contraceptive (OC) use at an early age may increase risk of breast cancer. Further, OC use appears to be particularly detrimental in young women with a family history. We have preliminary data suggesting that BRCA1 mutation carriers have a much higher risk associated with OC use than non- carriers. Such a detrimental effect of OC use in BRCA1 mutation carriers could be due to increased breast cell proliferation in these women. Experimental evidence suggests that BRCA1 may be a hormonally induced negative growth regulator. We propose to conduct a population-based study to determine the ratio of relative risk of breast cancer associated with OC use in BRCA1 mutation carriers and the relative risk of breast cancer associated with OC use in non-carriers. This information can subsequently be used to determine the relative risk of breast cancer associated with OC use in BRCA1 mutation carriers. The secondary aims of this study are to determine whether other hormonal risk factors such as selected reproductive factors and physical exercise differentially affect breast cancer risk in BRCA1 mutation carriers and non-carriers. This study will provide valuable epidemiologic information regarding the role of BRCA1 in breast cancer etiology, and could yield important results in developing intervention regimens and appropriate counseling for women with a BRCA1 mutation.