Leveraging Diversity in Cancer Epidemiology Cohorts and Novel Methods to Improve Polygenic Risk Scores

摘要 在不同种族/民族人群中，某些癌症的负担存在明显差异。为 例如，与欧洲血统的人相比，非裔美国人的比例高出约67% 前列腺癌发病率和亚太岛民男女分别高出70%和95% 肝癌的发病率分别为60.00%和60.00%。不同种族/民族之间癌症负担的差异 都归因于遗传、环境和社会因素的相互作用。尽管存在这样的差距，但一个 大多数基因研究都集中在欧洲血统的个体上。而全基因组关联 研究(Gwas)已经成功地确定了1000个癌症风险基因，它们主要集中在个人身上 欧洲血统的。不同种族/民族人口的代表性不足限制了翻译 全球气候变化网络研究结果对世界人口的潜在影响。应用在欧洲血统个体中发展起来的PRS 可能导致风险预测有偏差，并进一步加剧健康差距，因为 对高危人群的评估不准确。在这里，我们建议解决对 通过应用新的方案，在多个种族/民族之间建立和评估适当的方案 对以下六个大规模、长期队列的方法：多民族队列(MEC)；德皇 老年遗传流行病学研究资源(GERA)队列；妇女健康倡议； 哈佛护士健康研究(NHS)；哈佛健康专业人员后续研究(HPFS)；以及 前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验(PLCO)。总而言之，这些群体包括超过 300,000人(100,000名非欧洲人)和91,000起癌症病例(24,000名非欧洲人)。这个 这些群体中的个人来自五个种族/民族：非洲裔美国人、拉丁裔、日本人、土著 人口和欧洲血统。在关注癌症结果的同时，我们将利用这些独特的和 广泛的资源，用于开发构建和评估方案的方法，以及重要的翻译、评估 在多民族人群中，癌症的绝对和超额相对风险与已确定的危险因素共同作用。 为了便于访问已开发的管道和数据资源，我们将遵循F.A.I.R.分析原则，同时 与协调中心和其他研究地点一起参加。最终，构建和评估风险 非欧洲血统人群中的模型对于扩大基因组医学对人类的影响至关重要 健康。

Abstract There are stark differences in the burden of certain cancers across racial/ethnic populations. For example, in comparison to individuals of European ancestry, African American men have a ~67% higher incidence rate of prostate cancer and Asian/Pacific Islander men and women have a 70% and 95% higher incidence rate of liver cancer, respectively. These disparities in the burden of cancer across racial/ethnic groups have been attributed to an interplay of genetic, environmental, and social factors. Despite such disparities, a majority of genetic research has focused on individuals of European ancestry. While genome-wide association studies (GWAS) have successfully identified >1000 risk loci for cancer, they have focused primarily on individuals of European ancestry. The inadequate representation of diverse racial/ethnic populations limits the translational potential of GWAS findings to the world's populations. Applying PRS developed in European ancestry individuals to other populations may result in biased risk prediction, and further exacerbate health disparities due to inaccurate assessment of individuals at high risk of disease. Here, we propose to address the drastic need for appropriate PRS construction and evaluation across multiple race/ethnic groups by applying new PRS approaches to the following six large-scale, longstanding cohorts: the Multiethnic Cohort (MEC); the Kaiser Resource for Genetic Epidemiology Research on Aging (GERA) cohort; the Women's Health Initiative (WHI); the Harvard Nurses Health Studies (NHS); the Harvard Health Professionals Follow-Up Study (HPFS); and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Together, these cohorts include over 300,000 individuals (100,000 non-Europeans) and 91,000 incident cancer cases (24,000 non-Europeans). The individuals in these cohorts are from five racial/ethnic groups: African Americans, Latinos, Japanese, Native Populations, and European ancestry. While focusing on cancer outcomes, we will utilize these unique and extensive resources to develop methods to construct and evaluate PRS, and importantly for translation, estimate absolute and excess relative risk of cancer jointly for PRS and established risk factors in multiethnic populations. To facilitate access to developed pipelines and data resources, we will follow F.A.I.R. analytic principles while participating with the Coordinating Center and other study sites. Ultimately, constructing and evaluating risk models in non-European ancestry populations is essential to broaden the impact of genomic medicine on human health.