Her2 status of breast cancer in diverse populations: improving genetic prediction and understanding molecular correlates

不同人群中乳腺癌的 Her2 状况：改善遗传预测并了解分子相关性

• 批准号: 10660883
• 负责人: Laura Fejerman
• 金额: $ 46.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660883
• 关键词: African; Asian; Asian Americans; Asian ancestry; Asian population; Breast Cancer Genetics; Breast Cancer Patient; Breast Cancer Risk Factor; Cancer Etiology; Cancer Prognosis; Categories; Censuses; Cessation of life; Chinese; Colombian; Data; Development; Diagnosis; Disease; ERBB2 gene; Ensure; Epidermal Growth Factor Receptor; Equity; Ethnic Origin; Etiology; European; Frequencies; Gene Expression; Genes; Genetic; Genetic Complementation Test; Genetic Polymorphism; Genetic study; Genome; Genotype; Germ-Line Mutation; Goals; Hispanic; Hispanic Populations; Hormone Receptor; Human; Human Genetics; Incidence; Indigenous American; Individual; Knowledge; Latin American; Latina; Latina Population; Malaysian; Malignant Neoplasms; Mammary Neoplasms; Medicine; Mexican; Modeling; Modernization; Molecular; Not Hispanic or Latino; Outcome; Pacific Islander; Participant; Pathway Analysis; Patients; Pattern; Pertuzumab; Peruvian; Population; Population Heterogeneity; Prevention strategy; Public Health; Race; Reporting; Research; Sampling; Singapore; Testing; The Cancer Genome Atlas; Tissues; Trastuzumab; United States; Variant; Woman; Work; black women; breast cancer genomics; cancer risk; clinically significant; cohort; follow-up; genetic predictors; genetic variant; genome wide association study; high risk; hormone receptor-positive; improved; in silico; individualized prevention; insight; lapatinib; malignant breast neoplasm; migration; polygenic risk score; precision medicine; targeted treatment; transcriptome; transcriptomics; treatment strategy; tumor

PROJECT SUMMARY Breast cancer is the most common cancer in women and the second leading cause of cancer death in the United States (US). Although women included in the US Census racial/ethnic categories Hispanic/Latina (H/L) and Asian American/Pacific Islander (AA/PI) have relatively low breast cancer incidence compared to non-Hispanic White (NHW) women, multiple studies have reported a higher proportion of human epidermal growth factor receptor positive (HER2+) tumors in these groups (18-30%) compared to NHWs (14-18%). Expression of HER2 is clinically significant because it determines if a patient can receive targeted treatment. HER2+ disease, independent of hormone receptor (HR) status, is also associated with poor outcome compared to the most common HR+ HER2- subtype. The use of European-centric data to predict cancer risk and prognosis in non- Europeans remains a critical barrier for equity in the implementation of precision medicine. Overall, there is a gap in knowledge regarding the genetic factorsand molecular correlates relevant to the etiology of HER2+ breast cancer in diverse populations. Supported by a) our previous work showing a consistent association between Indigenous American ancestry and HER2+ subtypes in H/L breast cancer patients, b) the higher proportion of HER2+ tumors described in AA/PI and Asian populations, c) the closer genetic distance between these populations relative to European groups, and d) promising preliminary data, we hypothesize that germline variants more common in Indigenous American and Asian genomes contribute to the higher risk of HER2 amplification/expression in breast tumors of individuals with these ancestries. To test this hypothesis, we propose to integrate and leverage our own existing studies for a total of 17,049 cases (~4,200 HER2+) and 15,409 controls for discovery, and the NCI’s Confluence Project Data for replication (~600,000 cases and controls combined). Our main goal is to discover germline genetic variants contributing to the higher incidence of HER2+ breast cancer in women of Latin American and Asian heritage. To achieve this goal, we will 1) identify germline variation associated with HER2+ breast cancer in H/L and Asian women and replicate across diverse ancestries, 2) develop, validate, and test trans-ancestry and ancestry-specific polygenic risk scores for HER2+ disease, and 3) identify genes associated with HER2+ breast cancer risk in H/L and Asian women. The results of our study will lead to the discovery of genetic factors contributing to the observed HER2 subtype-ancestry association in women of Indigenous American and Asian ancestry for improved prediction, and provide a better understanding of HER2+ tumor etiology, which could lead to improved precision prevention strategies and the development of new targeted treatments for HER2+ disease.

项目概要 乳腺癌是女性最常见的癌症，也是美国癌症死亡的第二大原因 尽管女性被纳入美国人口普查种族/族裔类别中，但西班牙裔/拉丁裔 (H/L) 和 与非西班牙裔人相比，亚裔美国人/太平洋岛民 (AA/PI) 的乳腺癌发病率相对较低 白人（NHW）女性，多项研究报告人类表皮生长因子比例更高 与 NHW (14-18%) 相比，这些组中受体阳性 (HER2+) 肿瘤 (18-30%) 的 HER2 表达。 具有临床意义，因为它决定了患者是否可以接受 HER2+ 疾病的靶向治疗， 与激素受体 (HR) 状态无关，与大多数患者相比，也与不良结果相关 常见的 HR+ HER2- 亚型使用以欧洲为中心的数据来预测非癌症风险和预后。 总体而言，欧洲人仍然是实施精准医疗的关键公平障碍。 关于与 HER2+ 乳腺癌病因相关的遗传因素和分子相关性的知识差距 a）我们之前的研究表明，不同人群中的癌症之间存在一致的关联。 H/L 乳腺癌患者中具有美国原住民血统和 HER2+ 亚型，b) 的比例较高 AA/PI 和亚洲人群中描述的 HER2+ 肿瘤，c) 这些人群之间的遗传距离更近 相对于欧洲群体的人口，以及 d）有希望的初步数据，我们已经追寻了种系 美洲原住民和亚洲基因组中更常见的变异导致 HER2 风险更高 为了检验这一假设，我们提出了具有这些血统的个体的乳腺肿瘤中的扩增/表达。 整合和利用我们现有的总共 17,049 例病例（约 4,200 例 HER2+）和 15,409 例的研究 用于发现的控制，以及用于复制的 NCI Confluence 项目数据（约 600,000 个病例和控制 我们的主要目标是发现导致 HER2+ 发病率较高的种系遗传变异。 拉丁美洲和亚洲血统女性的乳腺癌 为了实现这一目标，我们将 1) 确定种系。 H/L 和亚洲女性中与 HER2+ 乳腺癌相关的变异，并在不同的血统中复制， 2) 开发、验​​证和测试 HER2+ 疾病的跨祖先和祖先特异性多基因风险评分，以及 3) 确定与 H/L 和亚洲女性 HER2+ 乳腺癌风险相关的基因。 将导致发现有助于观察到的 HER2 亚型-祖先关联的遗传因素 美洲原住民和亚洲血统的女性，以改进预测，并提供更好的理解 HER2+肿瘤病因学的研究，这可能会导致精确预防策略的改进和开发 针对 HER2+ 疾病的新靶向治疗。