Circadian Genes and Breast Cancer in African Americans and Caucasians

非裔美国人和白种人的昼夜节律基因与乳腺癌

• 批准号: 8636314
• 负责人: Ann Hsing
• 金额: $ 7.42万
• 依托单位: CANCER PREVENTION INSTIT OF CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636314
• 关键词: Affect; African; African American; Breast Cancer Prevention; Cancer Etiology; Carcinogens; Caucasians; Caucasoid Race; Chinese People; Circadian Rhythms; DNA Repair; Data; Diagnosis; Epidemiologic Studies; Estrogen Receptor 2; Estrogen Receptors; Estrogen receptor negative; Genes; Genetic; Hour; Human; Incidence; International Agency for Research on Cancer; Link; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of prostate; Meta-Analysis; Pattern; Population; Population Attributable Risks; Race; Receptor Signaling; Regression Analysis; Risk; Role; Single Nucleotide Polymorphism; Testing; Time; Variant; Woman; base; cancer risk; caucasian American; cohort; genetic variant; genome wide association study; high risk; malignant breast neoplasm; novel; outcome forecast; prevent; progesterone receptor negative; public health relevance; risk variant; shift work; tumor

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.

描述（由申请人提供）：非洲裔美国妇女受到更具侵略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，并且比其白种人的对应物的预后更差。这种种族差异的原因尚不清楚。 2007年，涉及昼夜节律中断的转移工作，这是人体在大约24小时周期运作的人体的昼夜定时模式，被归类为国际对人类的可能致癌物（2A组），该研究主要基于乳腺癌研究的发现。人体如何应对昼夜节律的干扰是部分原因是一组差异 调节昼夜节律（昼夜节律基因）的基因。这些昼夜节律基因可以影响ER信号传导和DNA损伤修复，这些因素与更高的乳腺癌风险有关。先前的研究还表明，非洲和非非洲人群之间的昼夜节律基因变化分布模式不同。我们假设30个昼夜节律基因的变化与非裔美国人和高加索妇女的乳腺癌风险有关。我们进一步假设，非洲裔美国人和高加索人之间的昼夜节律基因变异与侵略性乳腺癌亚型之间的关系有所不同，从而部分促成了这两个种族之间侵略性乳腺癌亚型的发病率差异。 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个对照，具有30个基因中3,800个变体的数据），用于全面的统计分析。使用来自AABC的数据，我们将确定非裔美国妇女中昼夜节律基因变异是否与乳腺癌的风险[总和和ER阴性和ER-阴性和ER- /孕酮受体（PR）阴性亚型有关（AIM 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小。同样，使用来自BPC3的数据，我们将确定昼夜节律变体是否与高加索妇女的ER-和ER-/Pr-/Pr-阴性乳腺癌的风险相关（AIM 2）。种族特异性分析的结果将用于确定昼夜节律基因变异（在AABC和BPC3妇女中均输入的2500个SNP）与非洲裔美国人和高卢人之间的ER-或ER-或ER-或ER-或ER-或ER-/PR阴性乳腺癌之间的关联是否有所不同，从而对这些侵略性乳腺癌的种族歧视造成了贡献（促成了这些侵略性乳腺癌的种族差异）。确定可以澄清的新型风险变体，即在非洲裔美国人和高加索人之间观察到的侵略性乳腺癌亚型种族差异的原因对于为制定乳腺癌策略提供重要信息特别有用 预防可能最大程度地减少两个种族群体的乳腺癌负担。