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.

项目摘要 乳腺癌是女性最常见的癌症，也是曼联癌症死亡的第二大原因 国家（美国）。 与非西班牙裔相比，亚裔美国/太平洋岛民（AA/PI）的乳腺癌事件相对较低 白人（NHW）妇女，多项研究报告了人类表皮生长因子的比例较高 与NHW相比，这些组的受体阳性（HER2+）肿瘤（18-30％）（14-18％）。 HER2的表达 具有临床意义，因为它确定患者是否可以接受目标治疗。 HER2+疾病， 与最大的结果相比 常见的HR+ HER2-亚型。使用以欧洲为中心的数据来预测非 - 欧洲人仍然是实施精密医学的公平障碍。总体而言，有一个 关于遗传因素和分子的知识差距与HER2+乳房的病因相关 潜水员种群的癌症。由a）我们以前的工作支持 H/L乳腺癌患者中的土著美国血统和HER2+亚型，b）较高的比例 HER2+肿瘤在AA/PI和亚洲种群中描述 相对于欧洲群体的人群以及d）有希望的初步数据，我们假设种系 在美国和亚洲土著基因组中更常见的变体促成了HER2的较高风险 这些祖先的个体的乳腺肿瘤的扩增/表达。为了检验这一假设，我们提出了 为了整合和利用我们自己现有的研究，总共有17,049例（约4,200 her2+）和15,409例 发现的控制和NCI的复制汇合项目数据（约600,000个案例和控件 结合）。我们的主要目标是发现造成HER2+较高事件的种系遗传变异 拉丁美洲和亚洲遗产女性的乳腺癌。为了实现这一目标，我们将1）确定种系 H/L和亚洲妇女中与HER2+乳腺癌相关的变异，并在潜水员的祖先中复制， 2）开发，验证和测试HER2+疾病的反式委托和祖先特异性多基因风险评分，以及 3）确定H/L和亚洲妇女中与HER2+乳腺癌风险相关的基因。我们研究的结果 将导致发现有助于观察到的HER2亚型术的遗传因素 美国土著美国和亚洲血统的妇女以改进预测，并提供更好的理解 HER2+肿瘤病因，这可能导致改善的预防策略和发展 HER2+疾病的新目标治疗。