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

描述（由申请人提供）：乳腺癌是全球女性中最常见的癌症诊断，与非洲裔美国人（AA）和拉丁美洲人（LA）女性相比，白人美国人（CA）女性的发病率更高。然而，AA和LA女性更容易患上侵袭性癌症（即，三阴性乳腺癌（TNBC））。祖先的混合和遗传易感性都与乳腺癌的风险有关，但迄今为止发现的大多数遗传变异都位于非乳腺癌组织中。 具有未确定功能意义的蛋白质编码区。因此，迫切需要替代方法来为生物功能和致癌作用提供新的见解。中间表型，如代谢产物谱，可能被证明是一个有用的替代方法。代谢产物是细胞调节过程的最终产物，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。我们提出了一个创新的代谢组学研究，包括发现组件和验证组件，以调查乳腺癌发生中无法解释的种族/民族差异。该研究旨在解决总体假设，即CA，AA和LA女性的血浆代谢产物谱不同，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是由遗传易感性和祖先的混合修改。在发现部分，将入组900例乳腺癌病例（CA、AA和LA病例各300例）和900例人种/种族、年龄和居住地匹配的对照，并采集治疗前血样进行代谢物分析和基因分型。代谢组学分析将在Metabolon，Inc.进行。使用GC/MS和LC/MS平台。将使用Illumina Custom GoldenGate OPA 1536-plex平台进行基因分型。将从MD安德森临床数据库中提取临床数据和肿瘤特征，包括ER、PR和HER 2表达状态。将从患者病史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。该部分将评估代谢特征在乳腺癌风险种族/民族差异中的作用，以及这种差异在多大程度上可以通过祖先混合物和先前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-乳腺癌关联是否不同。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和墨西哥裔美国人队列）中进行验证。验证部分包括450例乳腺癌病例（CA、AA和LA病例各150例）和450例对照，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相关性。拟议的研究将使关键的差距缩小在理解乳腺癌的种族/民族差异的潜在生物学。

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.