Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

摘要 本申请是为了响应特别利益通知（NOSI）而提交的，该通知被确定为 NOT-CA-22-056。急性淋巴细胞白血病（ALL）是最常见的儿科癌症， 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， 幸存者面临着终身治疗相关的疾病。拉丁裔的孩子有最高的 在美国，ALL的风险增加最快，生存率低于非拉丁裔白人;然而， 发病率和结果的种族差异尚未得到充分了解。阐明拉丁美洲人ALL的风险增加 在拉丁裔和非拉丁裔人群中，儿童可能揭示ALL病因的新见解， 突出疾病预防潜在途径。我们假设，生殖系遗传变异发挥了重要作用， 在拉丁美洲人的ALL风险增加中起着至关重要的作用，这种风险是通过美洲原住民血统传递的， 在欧洲殖民美洲期间，美洲原住民选择了ALL风险等位基因， 它们对新感染的免疫反应的有益作用。我们收集了有史以来最大的案件- 拉丁美洲儿童ALL的对照组，包括来自三个独立研究机构的5,400多例病例和27,000例对照。 在加州的研究，加上在得克萨斯州的研究，儿童肿瘤组/圣裘德儿童研究医院， 和危地马拉。在我们的第一个目标，我们将执行三个互补的方法来发现新的共同点， 与儿童ALL相关的风险基因座：i）全基因组关联研究（GWAS）荟萃分析，ii） 混合映射，以利用最近拉丁美洲基因组的混合性质，和iii）转录组- 广泛的关联研究，以确定新的基因座，并查明在已知和新的风险区域的致病基因。在 我们的第二个目标是，我们将根据它们与当地土著人的联系来描述遗传变异。 美国血统，以及他们是否表现出对美洲原住民的定向自然选择的证据 人口树的分支。我们还将描述常见变异体对 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 (PRS)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纳入 流行病学分析，通过解释免疫相关ALL风险模型中的常见（PRS）遗传变异， 拉丁美洲人和非拉丁美洲白人的相关风险因素，包括剖宫产和子宫内巨细胞病毒 感染，这两种感染都对拉丁美洲人的ALL风险有更强的影响，并且是潜在的可改变的风险 因素这项研究的结果将阐明儿童ALL的一般病因，以及儿童ALL发病率增加的原因。 拉丁裔儿童ALL的风险，这将有助于缓解这种种族差异，并可能为未来的方法提供信息 儿童白血病的预防。

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.