Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

摘要 急性淋巴细胞白血病 (ALL) 是最常见的儿科癌症，尽管治疗方法取得了进步，但它 仍然是美国儿童死亡的主要原因之一，幸存者面临着巨大的压力 与终生治疗相关的疾病。拉丁裔儿童的患病风险最高且增长最快 全部生活在美国，且存活率低于非拉丁裔白人；然而，这种发病率和发病率的种族差异 结果尚未完全理解。阐明拉丁裔儿童患 ALL 的风险增加可能会揭示新的见解 拉丁裔和非拉丁裔人群中 ALL 的病因学，并可能突出疾病的潜在途径 预防。我们假设种系遗传变异在 ALL 风险增加中发挥重要作用 拉丁裔，这种风险是通过美洲原住民血统传递的，并且所有风险等位基因都是在原住民中选择的 在欧洲殖民美洲期间，美国人由于其对免疫反应的有益影响 新的感染。我们收集了有史以来最大的拉丁裔儿童 ALL 病例对照组，其中包括超过 来自加利福尼亚州三项独立研究的 5,400 例病例和 27,000 例对照，以及德克萨斯州、儿童医院的研究 肿瘤学组/圣。裘德儿童研究医院和危地马拉。在我们的第一个目标中，我们将执行三个 发现与儿童 ALL 相关的新常见风险位点的补充方法：i) 基因组- 广泛关联研究（GWAS）荟萃分析，ii）混合映射以利用最近混合的 拉丁裔基因组的性质，以及 iii) 一项全转录组关联研究，以确定新的基因座并查明 已知和新风险区域的致病基因。在我们的第二个目标中，我们将描述遗传变异的特征 他们与当地美洲原住民血统的联系以及他们是否表现出方向性的证据 人类种群树的美洲原住民分支上的自然选择。我们还将描述 通过综合分析，常见变异对儿童 ALL 风险的总体影响以及该风险如何因种族而异 拉丁裔和非拉丁裔白人的 ALL 多基因风险评分 (PRS) 模型。最后，我们将合并 通过考虑 ALL 风险中的常见 (PRS) 遗传变异，将我们的遗传发现纳入流行病学分析 拉丁裔和非拉丁裔白人免疫相关危险因素模型，包括剖腹产和子宫内分娩 巨细胞病毒感染，这两种病毒感染对拉丁美洲人的 ALL 风险都有更强的影响，并且有可能 可改变的风险因素。这项研究的结果将揭示儿童 ALL 的一般病因和 拉丁裔儿童患 ALL 的风险增加，这将有助于缓解这种种族差异，并可能为未来提供信息 儿童白血病预防方法。

ABSTRACT 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.