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

项目摘要或摘要 越来越多的证据表明，多基因风险分数(Prs)，或疾病遗传风险的综合测量 基于全基因组关联研究(GWAS)的发现，可能有助于预测广泛的 在普通人群中发现了一系列慢性健康问题。但是，预测延迟是否有用呢？ 影响儿童、青少年和青壮年(CAYA)癌症幸存者的风险？最近，我们展示了 在普通人群中进行的基于GWAS的社区卫生服务对以下疾病的风险预测相对较差 幸存者中的各种CHC，部分原因是他们没有考虑特定疗效的修饰作用 癌症治疗对慢性丙型肝炎的遗传风险，即治疗特有的遗传效应。到目前为止，还没有 分析方法弥合了这一研究差距：这个项目具有创新性，因为它旨在开发一种新的方法 对于PR来说，这也可以纳入治疗特有的遗传效应。建议的总体目标是 该项目是创建新的遗传风险预测器，将在 治疗特异性遗传效应对CAYA人群慢性丙型肝炎风险的公平预测 癌症幸存者。我们将使用10个CHC和复杂性状的初步集合来研究这种方法， 包括随后的癌症以及心血管和内分泌疾病。这个项目的长期目标是 将这些新开发的针对治疗的遗传风险预测指标应用于个性化的后续护理 幸存者计划，响应RFA-CA-20-028应用程序域5(风险开发 晚期效应的预测指标)和6(制定针对性干预措施以减轻癌症负担)。 利用约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工作 具体目标：(1)为每一种疾病编制一份针对治疗特定遗传效应的综合目录 选定的表型；(2)开发和评估相应的“幸存者富集型”PR，其中包括这些 治疗特有的遗传效应；以及(3)评估富含幸存者的PR是否可以减少 种族/少数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 将执行战略性的全基因组关联分析，以确定其风险关联的遗传变异 通过治疗性暴露对氯化氢化合物进行修饰。然后，我们打算调整现有的方法，以改进 将来自普通种群的发现与一般种群的发现相结合的群体间推广性 对幸存者进行基因分析的结果。这些幸存者丰富PR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，鉴于特定于治疗的遗传效应可能是 跨种族，我们将在种族/少数民族幸存者亚群中评估幸存者丰富的PR 传统上被排除在以欧洲为中心的全球气候变化框架外。这项拟议中的研究具有重要的潜在帮助 使用特定于治疗的遗传风险评分来识别具有不良健康后果高风险的幸存者， 将代表着比目前的生存护理指南更重要的进步。

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.