Racial/ethnic disparity in breast cancer: can metabolic profiles play a role?

描述(申请人提供)：乳腺癌是全世界女性中最常见的癌症诊断，与非裔美国人(AA)和拉丁裔美国人(LA)女性相比，高加索美国人(CA)女性的发病率更高。然而，AA和LA女性更有可能在早期患上侵袭性癌症(即三阴性乳腺癌(TNBC))。祖先的混合基因和遗传易感性都与乳腺癌风险有关，但到目前为止发现的大多数基因变异都位于非 具有未知功能意义的蛋白质编码区。因此，迫切需要替代的方法来为生物学功能和癌症发生提供新的见解。中间表型，如代谢物图谱，可能被证明是一种有用的替代方法。代谢物是细胞调控过程的最终产物，因此它们的浓度可以被视为遗传和环境相互作用的最终净结果。我们提出了一项代谢组学的创新研究，包括一个发现部分和一个验证部分，以调查乳腺癌发生中原因不明的种族/民族差异。这项研究旨在解决一个重要的假设，即CA、AA和LA女性的血浆代谢物谱不同，代谢特征可以解释乳腺癌风险的一些种族/民族差异。我们进一步假设，代谢物相关的乳腺癌风险受遗传易感性和祖先混合因素的影响。在发现部分，900例乳腺癌患者(CA、AA和LA患者各300例)和900名种族/民族、年龄和居住地匹配的对照人员将通过收集治疗前血液样本进行代谢物分析和基因分型。代谢组学分析将在新陈代谢公司使用GC/MS和LC/MS平台进行。基因分型将使用Illumina Custom GoldenGate OPA 1536-Plex平台进行。临床数据和肿瘤特征，包括ER、PR和HER2表达状态，将从MD Anderson临床数据库中提取。流行病学数据，包括身高和体重史，饮酒和家族癌症史，将从患者历史数据库中提取。这一部分将评估代谢特征在乳腺癌风险的种族/民族差异中的作用，以及这种差异可以在多大程度上由祖先的混合和以前GWAS报告的遗传易感性来解释。我们还将评估TNBC和非TNBC的代谢物-乳腺癌相关性是否不同。最有希望的5-10种代谢物将被纳入两项基于人群的前瞻性队列研究(PLCO和墨西哥美国队列)进行验证。验证部分包括450例乳腺癌病例(CA、AA和LA病例各150例)和450名对照，将评估这些代谢物与乳腺癌风险的相关性，以及随访时间是否可以改变乳腺癌的相关性。这项拟议的研究将有助于缩小在理解乳腺癌种族/民族差异的潜在生物学方面的差距。

DESCRIPTION (provided by applicant): Breast cancer, the most common cancer diagnosis among women worldwide, occurs in greater incidence among Caucasian American (CA) women compared to African American (AA) and Latina American (LA) women. However, AA and LA women are more likely to develop an aggressive form of cancer (i.e., triple- negative breast cancer (TNBC)) at an early age. Both ancestral admixture and genetic susceptibility have been linked to breast cancer risk, but most of the genetic variants identified so far are located in non protein encoding regions with undetermined functional significance. Thus, alternative approaches are critically needed to provide new insight to biological function and carcinogenesis. Intermediate phenotypes, such as metabolite profiles, may prove to be a useful alternative approach. Metabolites are end products of cellular regulatory processes, so their concentrations can be regarded as the ultimate net results of genetic and environmental interactions. We propose an innovative study of metabolomics involving a discovery component and a validation component to investigate the unexplained racial/ethnic disparity in breast cancer occurrence. The study is designed to address the overarching hypothesis that plasma metabolite profiles differ in CA, AA, and LA women and that metabolic signatures can explain some of the racial/ethnic differences in breast cancer risks. We further hypothesize that the metabolite-related breast cancer risks are modified by genetic susceptibility and ancestral admixture. In the discovery component, 900 breast cancer cases (300 each of CA, AA, and LA cases) and 900 race/ethnicity, age, and residence matched controls will be enrolled with collection of a pre-treatment blood sample for metabolite analysis and genotyping. Metabolomic profiling will be conducted at Metabolon, Inc. using GC/MS and LC/MS platforms. Genotyping will be conducted using the Illumina Custom GoldenGate OPA 1536-plex platform. Clinical data and tumor characteristics, including ER, PR, and HER2 expression status, will be extracted from the MD Anderson clinical database. Epidemiological data, including height and weight history, alcohol drinking, and family cancer history, will be extracted from the Patient History Database. This component will evaluate the role of metabolic profiles in racial/ethnic disparity in breast cancer risk and the extent to which this disparity may be explained by ancestral admixture and previous GWAS-reported genetic susceptibility. We will also evaluate whether the metabolite-breast cancer associations differ for TNBC and non-TNBC. The most promising 5-10 metabolites will be included for validation in two population-based prospective cohort studies (PLCO and Mexican American Cohort). The validation component, including 450 breast cancer cases (150 each of CA, AA, and LA cases) and 450 controls, will evaluate the associations of these metabolites with breast cancer risk and whether length of follow-up could modify the breast cancer associations. The proposed research will enable a critical narrowing of the gap in understanding the underlying biology of racial/ethnic differences in breast cancer.