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

用于预测儿童、青少年和年轻成年癌症幸存者晚期效应的治疗特异性遗传风险评分

基本信息

批准号：
10273416
负责人：
Cindy Im
金额：
$ 2.25万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10273416
关键词：
Accounting Adolescent and Young Adult American Cancer Burden Cancer Survivor Cancer Survivorship Cardiovascular Diseases Caring Catalogs Childhood Childhood Cancer Survivor Study Chronic Cohort Studies Complex Counseling Data Development Disease Early Intervention Endocrine System Diseases Ethnic group European Evaluation Frequencies General Population Genetic Genetic Risk Goals Guidelines Health Heritability Human Genetics Individual Integration Host Factors Intervention Joints Journals Knowledge Late Effects Life Long-Term Survivors Malignant Neoplasms Measures Meta-Analysis Methods Modality Modeling Neoplasms Outcome Performance Phenotype Population Population Study Premature Menopause Public Health Reporting Research Risk Risk Factors Saint Jude Children&apos s Research Hospital Sampling Signal Transduction Single Nucleotide Polymorphism Stroke Subgroup Survivors Target Populations Therapeutic Update Variant Weight analytical method base cancer therapy clinical decision-making clinical risk cohort curative treatments disorder risk ethnic minority population follow-up genetic analysis genetic association genetic risk factor genetic variant genome wide association study genome-wide genomic data high risk improved innovation malignant breast neoplasm novel personalized care phenotypic data polygenic risk score precision medicine preventive intervention programs racial and ethnic racial diversity risk prediction risk stratification screening survivorship tool trait

项目摘要

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.

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，幸存者中存在各种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来改进 PRS的跨人群概括性，以将来自普通人群GWAS的联合收割机发现与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。