Circadian Genes and Breast Cancer in African Americans and Caucasians

描述(由申请者提供)：非裔美国女性不成比例地受到更具侵袭性的乳腺癌亚型的影响，例如雌激素受体(ER)和三重阴性癌症，并且比高加索女性更有可能有更差的预后。造成这种种族差异的原因尚不清楚。2007年，涉及打乱昼夜节律的倒班工作被国际癌症研究机构归类为可能对人类致癌(第2A组)，这主要是基于乳腺癌研究的结果。昼夜节律是人体每天的计时模式，大约以24小时为一个周期。人体对昼夜节律紊乱的反应在一定程度上是由于30个 调节昼夜节律的基因(昼夜节律基因)这些昼夜节律基因可以影响ER信号和DNA损伤修复，这些因素与乳腺癌的风险更高有关。以前的研究还表明，昼夜节律基因变异的分布模式在非洲和非非洲人群中不同。我们假设，30个昼夜节律基因的变异与非裔美国人和高加索女性患乳腺癌的风险有关。我们进一步假设，昼夜节律基因变异与侵袭性乳腺癌亚型之间的关系在非裔美国人和高加索人之间有所不同，因此在一定程度上导致了这两个种族之间侵袭性乳腺癌亚型发病率的差异。我们将利用非洲裔美国人乳腺癌联盟(AABC；3,200例，包括1,000例ER阴性病例和2,800例对照，30个基因中7,400个变异的数据)和乳腺癌和前列腺癌联合组织(BPC3；2,200个ER阴性病例和2,200个对照，30个基因中3,800个变异的数据)的现有基因数据对乳腺癌进行大规模研究，以进行全面的统计分析。使用AABC的数据，我们将确定昼夜节律基因变异是否与非裔美国女性患乳腺癌的风险相关(目标1)；我们专注于ER和ER/PR阴性亚型，因为三重阴性病例的数量很少。同样，使用来自BPC3的数据，我们将确定昼夜节律基因变异是否与高加索女性ER和ER/PR阴性乳腺癌的风险相关(目标2)。种族特异性分析的结果将被用来确定昼夜节律基因变异(在AABC和BPC3女性中都有2500个SNP)与ER或ER/PR阴性乳腺癌之间的关联在非裔美国人和高加索人中是否不同，从而在一定程度上导致这些侵袭性乳腺癌亚型的种族差异(目标3)。识别新的风险变异，可以澄清观察到的非裔美国人和高加索人之间侵袭性乳腺癌亚型的种族差异的原因，将特别有助于为制定乳腺癌治疗策略提供重要信息。 预防可能会将两个种族群体的乳腺癌负担降至最低。

DESCRIPTION (provided by applicant): African American women are disproportionally affected by more aggressive subtypes of breast cancer, such as estrogen receptor (ER)- and triple negative cancers, and are more likely to have worse prognoses than their Caucasian counterparts. Reasons for this racial disparity are unclear. In 2007, shift work that involves disruption of the circadian rhythm, the body's diurnal pattern of timing that operates on about a 24-hour cycle, was classified as a probable carcinogen to humans (group 2A) by the International Agency for Research on Cancer based primarily on findings from breast cancer studies. How the body responds to circadian disruptions is due in part to variations in a set of 30 genes that regulate the circadian rhythm (circadian genes). These circadian genes can influence ER signaling and DNA damage repair, factors that have been linked to a higher risk of breast cancer. Previous studies have also shown that the distribution patterns of variations in the circadian genes differ between African and non-African populations. We hypothesize that variations in the 30 circadian genes are associated with breast cancer risk in African American and Caucasian women. We further hypothesize that the relationship between circadian gene variants and aggressive breast cancer subtypes differ between African Americans and Caucasians, thereby contributing partly to the disparity of incidence rates of the aggressive breast cancer subtypes seen between these two racial groups. We will test these hypotheses by conducting a large study of breast cancer using existing genetic data on African American women from the African American Breast Cancer Consortium (AABC; 3,200 cases, including 1,000 ER-negative cases, and 2,800 controls with data on 7,400 variants in the 30 genes) and Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3; 2,200 ER-negative cases and 2,200 controls with data on 3,800 variants in the 30 genes) for a comprehensive statistical analysis. Using data from the AABC, we will determine whether circadian gene variants are associated with risk of breast cancer [total and ER-negative and ER- /progesterone receptor (PR)-negative subtypes] in African American women (Aim 1); we focus on ER- and ER-/PR-negative subtypes because numbers of triple negative cases are small. Similarly, using data from BPC3, we will determine whether circadian gene variants are associated with risk of ER- and ER-/PR-negative breast cancers in Caucasian women (Aim 2). Results of the race-specific analysis will be used to determine whether the associations between circadian gene variants (2,500 SNPs typed in both AABC and BPC3 women) and ER- or ER-/PR-negative breast cancers differ between African Americans and Caucasians, thereby contributing partly to the racial disparity of these aggressive breast cancer subtypes (Aim 3). Identifying novel risk variants that can clarify reasons for the observed racial disparity of aggressive breast cancer subtypes between African Americans and Caucasians will be particularly useful for providing important information for developing strategies for breast cancer prevention that might minimize the burden of breast cancer in both racial groups.