Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

摘要 本申请是对特别利益通知(NOSI)的回应，该通知被确认为 不是-CA-22-056。急性淋巴细胞白血病(ALL)是最常见的儿科癌症，尽管 尽管在治疗方面取得了进展，但它仍然是美国儿童死亡的主要原因之一，以及 幸存者面临着严重的终身治疗相关疾病。拉丁裔儿童的比例最高 在美国，风险上升最快，存活率低于非拉丁裔白人；然而，这一点 发病率和预后方面的种族差异还没有完全了解。阐明拉丁裔ALL风险增加 在拉丁裔和非拉丁裔人群中，儿童可能会对ALL的病因提出新的见解，并可能 突出疾病预防的潜在途径。我们假设生殖系遗传变异对 拉美人ALL风险增加的关键作用，即这种风险是通过美洲原住民祖先遗传的，以及 在欧洲殖民美洲期间，所有的风险等位基因都是在美洲原住民中选择的，因为 它们在对新感染的免疫反应中的有益作用。我们组装了有史以来最大的箱子- 儿童时期的控制组全部为拉丁裔，包括3个独立病例的5,400多例和27,000例对照 在加利福尼亚州的研究，加上在德克萨斯州的研究，儿童肿瘤学组织/圣裘德儿童研究医院， 和危地马拉。在我们的第一个目标中，我们将执行三种互补的方法来发现新的共同点 与儿童ALL相关的风险基因：i)全基因组关联研究(Gwas)荟萃分析，ii) 混合作图，以利用最近混合的拉丁裔基因组的性质，以及iii)转录组- 广泛的关联研究，以确定新的基因座，并在已知和新的危险区域定位原因基因。在……里面 我们的第二个目标是，我们将根据基因变异与当地原住民的联系来描述它们的特征 美国人的祖先和他们是否表现出美洲原住民定向自然选择的证据 人类种群树的分支。我们还将描述常见变体对 通过多基因风险评分的综合建模，了解儿童ALL风险及其随种族的变化情况 (PRS)面向所有拉丁裔和非拉丁裔白人。最后，我们将把我们的基因发现整合到 流行病学分析，通过考虑免疫-疾病所有风险模型中常见的(PR)基因变异。 拉丁裔和非拉丁裔白人的相关危险因素，包括剖腹产和宫内巨细胞病毒 感染，这两者对拉丁裔的所有风险都显示出更强的影响，并且都是潜在的可改变的风险 各种因素。这项研究的结果将有助于阐明儿童ALL的病因学和儿童增生性疾病的病因 拉美裔儿童的ALL风险，这将有助于缓解这种种族差距，并可能为未来的做法提供参考 预防儿童白血病。

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-056. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it is still one of the leading causes of childhood death in the United States (US), and survivors face significant lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native Americans during European colonization of the Americas due to their beneficial effects on immune response to new infections. We have assembled the largest ever case- control set of childhood ALL in Latinos, including over 5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome-wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed nature of Latino genomes, and iii) a transcriptome- wide association study to identify novel loci and to pinpoint causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in terms of their association with local Native American ancestry and whether they exhibit evidence of directional natural selection on the Native American branch of the human population tree. We will also characterize the aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk models for immune- related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future approaches for childhood leukemia prevention.