Treatment-specific genetic risk scores for late effects prediction in childhood,adolescent, and young adult cancer survivors

项目概要或摘要 越来越多的证据表明，多基因风险评分（PRS），或疾病遗传风险的综合措施， 基于全基因组关联研究（GWAS）的发现， 一系列的慢性健康状况（CHC）在一般人群。但是，PRS对于预测晚期 影响儿童、青少年和年轻成人（CAYA）癌症幸存者的风险？最近，我们发现 在一般人群中进行的基于GWAS的PRS是相对较差的风险预测因子， 幸存者中的各种CHC，部分原因是他们没有考虑特定治疗药物的修饰作用， 癌症治疗对CHC遗传风险的影响，即，治疗特异性遗传效应。迄今为止，没有任何现有的 分析方法弥补了这一研究空白：该项目是创新的，因为它旨在开发一种新的方法 对于PRS，也可以包含治疗特异性遗传效应。建议的总体目标 一个项目是创造新的遗传风险预测因子，该因子将联合收割机中确定的遗传风险信号结合起来， 具有治疗特异性遗传效应的一般人群GWAS可公平预测CAYA中的CHC风险 癌症幸存者我们将使用一组初步的10个CHC和复杂性状来研究这种方法， 包括随后的癌症以及心血管和内分泌疾病。该项目的长期目标是 应用这些新开发的治疗特异性遗传风险预测因子， 针对幸存者的计划，响应RFA-CA-20-028应用领域5（风险发展 晚期效应的预测因素）和6（制定有针对性的干预措施，以减少癌症负担）。 利用来自约13，000名幸存者的现有遗传/表型数据，拟议的研究将进行以下研究 具体目标：（1）为每种治疗方法编制一个全面的治疗特异性遗传效应目录， 选择表型;（2）开发和评估相应的“生存者富集”PRS， 治疗特异性遗传效应;（3）评估生存者富集的PRS是否可以减少 对少数种族/民族人群幸存者的晚期效应风险预测。为了实现第一个目标，我们 将进行战略性的全基因组关联分析，以确定遗传变异， 通过治疗暴露来改变。然后，我们打算调整现有的方法，以改善 将一般人群GWAS的发现与联合收割机的发现结合起来的跨人群普适性 幸存者的基因分析结果。这些生存者富集的PRS的相对预测能力将是 在独立的幸存者样本中进行评估。最后，鉴于治疗特异性遗传效应可能是 跨种族，我们将在种族/少数民族幸存者亚组中评估幸存者丰富的PRS， 传统上被排除在欧洲中心的GWAS之外。拟议中的研究具有重要的潜力， 用治疗特异性遗传风险评分识别不良健康结局高风险的幸存者， 这将是对当前生存护理指南的一个重要进步。

PROJECT SUMMARY OR ABSTRACT There is growing evidence that polygenic risk scores (PRS), or aggregate measures of genetic risk for disease based on findings from genome-wide association studies (GWAS), may be useful in predicting risks for a wide array of chronic health conditions (CHCs) in the general population. But are PRS useful for predicting late effects risks in survivors of childhood, adolescent, and young adult (CAYA) cancer? Recently, we have shown that PRS based on GWAS conducted in the general population are relatively poor predictors of risks for various CHCs in survivors, in part because they do not consider the modifying effects of specific curative therapies for cancer on genetic risks for CHCs, i.e., treatment-specific genetic effects. To date, no existing analytic method bridges this research gap: this project is innovative because it aims to develop a new method for PRS that can also incorporate treatment-specific genetic effects. The overall objective of the proposed project is to create novel genetic risk predictors that combine established genetic risk signals identified in general population GWAS with treatment-specific genetic effects to equitably predict CHC risks in CAYA cancer survivors. We will investigate this approach using a preliminary set of ten CHCs and complex traits, including subsequent cancers and cardiovascular and endocrine diseases. The long-term goal of this project is to apply these newly developed treatment-specific genetic risk predictors to inform personalized follow-up care programs for survivors, which responds to RFA-CA-20-028 application domains 5 (development of risk predictors of late effects) and 6 (development of targeted interventions to reduce the burden of cancer). Utilizing existing genetic/phenotype data from ~13,000 survivors, the proposed study will pursue the following specific aims: (1) compile a comprehensive catalog of treatment-specific genetic effects for each of the selected phenotypes; (2) develop and evaluate corresponding “survivor-enriched” PRS that incorporate these treatment-specific genetic effects; and (3) assess whether survivor-enriched PRS can decrease disparities in late effects risk prediction in survivors from racial/ethnic minority populations. To accomplish the first aim, we will perform strategic genome-wide association analyses to identify genetic variants whose risk associations with CHCs are modified by therapeutic exposures. We then intend to adapt existing methods shown to improve the cross-population generalizability of PRS to combine discoveries from general population GWAS with results from genetic analyses in survivors. The relative predictive ability of these survivor-enriched PRS will be evaluated in an independent survivor sample. Lastly, given that treatment-specific genetic effects may be trans-ethnic, we will assess survivor-enriched PRS in racial/ethnic minority survivor subgroups that have been traditionally excluded from Eurocentric GWAS. The proposed research is significant in its potential to help identify survivors at high risk for adverse health outcomes with treatment-specific genetic risk scores, which would represent an important advance over current guidelines for survivorship care.