Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

摘要 急性淋巴细胞性白血病(ALL)是最常见的儿童癌症，尽管治疗取得了进展，但它 仍然是美国儿童死亡的主要原因之一，幸存者面临着重大的 终生与治疗相关的疾病。拉丁裔儿童患癌症的风险最高，增长最快。 都在美国，存活率低于非拉丁裔白人；然而，这种发病率和 结果还没有完全弄清楚。阐明拉美裔儿童ALL风险增加可能会揭示新的见解 在拉丁裔和非拉丁裔人群中ALL的病因学方面，并可能突出潜在的致病途径 预防。我们假设，生殖系遗传变异在增加的所有风险中起重要作用。 拉美人，这种风险是通过美洲原住民的祖先遗传的，并且所有的风险等位基因都是在原住民中选择的 美国人在欧洲殖民美洲期间，由于他们对免疫反应的有益影响 新的感染。我们已经收集了有史以来最大的儿童病例对照集合，所有人都是拉丁裔，包括 5,400例病例和27,000名对照，来自加利福尼亚州的三项独立研究，以及德克萨斯州的研究，儿童 肿瘤学小组/圣犹大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相关的新的共同危险基因的互补方法：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)一项转录组范围的关联研究，以确定新的基因座并精确定位 已知和新风险区域的因果基因。在我们的第二个目标中，我们将描述 他们与当地美洲原住民祖先的联系以及他们是否表现出方向性的证据 人类种群树中美洲原住民分支上的自然选择。我们还将描述 共同变异对儿童ALL风险的综合影响，以及这种影响如何因种族而异，通过 拉丁裔和非拉丁裔白人所有人的多基因风险分数(PR)模型。最后，我们将把 通过考虑所有风险中的常见(PR)基因变异，将我们的基因发现纳入流行病学分析 拉丁裔和非拉丁裔白人的免疫相关危险因素模型，包括剖腹产和宫内分娩 巨细胞病毒感染，这两种病毒对拉丁裔的所有风险都显示出更强的影响，并有可能 可更改的风险因素。这项研究的结果将有助于揭示儿童ALL的一般病因学和 拉美裔儿童患ALL的风险增加，这将有助于缓解这种种族差距，并可能为未来 预防儿童白血病的方法。

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.