Cytomegalovirus as an etiologic and clinico-pathogenic factor in childhood acute lymphoblastic leukemia

摘要 儿童急性淋巴细胞白血病(ALL)是儿童(0-14岁)最常见的癌症。尽管 随着治疗的改善，幸存者面临着终身与治疗的负面健康影响作斗争，使 预防是优先事项。缺乏可改变的病因一直是预防的主要障碍，但我们 最近一个突破性的(尽管是初步的)发现，新生儿巨细胞病毒(NCMV)感染 在一项有268例和270例儿童ALL的小型研究中，是儿童ALL的强烈风险因素(估计优势比=3.7 控制。在同一项研究中，我们还在治疗前诊断的肿瘤组织中发现了CMV序列。在……里面 此外，我们进行了一项基于人群的研究，将瑞典的医疗记录和癌症登记数据联系起来， 这表明早期CMV感染和儿童血液系统恶性肿瘤的相对风险超过10 诊断。我们建议在这里明确地评估CMV的流行病学和所有包括CMV的影响 在所有肿瘤基因组上。我们假设nCMV将导致所有的发病，并创建特定的 所有已知与病毒和传染性相关的肿瘤基因组中都存在突变特征 病因学。在我们的第一个目标中，我们将更好地定义nCMV感染作为一个所有风险因素的作用 超过3800个病例和4897个对照，考虑到其他危险因素，如出生体重、出生顺序、 分娩、ALL和父母年龄的多基因风险评分新生儿免疫表型，以及 孕妇孕期巨细胞病毒感染状况。我们还将评估CMV是否对更高的 与其他群体相比，拉丁裔ALL的风险更高。作为第二个目标，我们将对1020名儿童进行CMV检测 出生时受累，并与诊断时收集的所有肿瘤基因组相匹配。我们会调查的 APOBEC和重组酶激活基因(RAG)的存在，病毒相关突变 与nCMV阴性的儿童相比，nCMV阳性的肿瘤内的特征。这 研究将利用特殊资源，包括存档的新生儿血液样本和人口- 以儿童时期所有病例和对照以及孕中期采集的母亲血液样本为基础。在……里面 此外，拟议的研究受益于研究人群中携带A基因的高比例拉丁裔 儿童不成比例的负担ALL，包括先进的实验室技术，以识别新生儿和 母体CMV感染已在我们实验室提纯，并将直接评估突变标志 推测是由病毒引起的。巨细胞病毒是一种高度熟练的免疫操纵器。黄瓜花叶病毒的鉴定 儿童时期的致病因素ALL可以为预防白血病创造一个前所未有的靶点，要么通过 接种巨细胞病毒疫苗或操纵宿主对出生后巨细胞病毒感染的反应。在任何一种中 假设，这一提议将更好地描述CMV在儿童ALL和 从预防的角度来看，这将产生深远的影响。因为巨细胞病毒还会导致先天性听力损失和 除了白血病之外，我们的研究还将影响儿童健康，这是一系列其他神经学结果。

ABSTRACT Childhood acute lymphoblastic leukemia (ALL) is most common cancer in children (age 0- 14 years). Despite improvements in treatment, survivors face a lifelong battle with negative health effects of treatment, making prevention a priority. The lack of modifiable etiological factors has been a major barrier to prevention, but we recently made a groundbreaking (albeit preliminary) discovery that neonatal cytomegalovirus (nCMV) infection is a strong risk factor for childhood ALL (estimated odds ratio = 3.7) in a small study with 268 cases and 270 controls. In the same study, we also found CMV sequences within pre-treatment diagnostic tumor tissue. In addition, we conducted a population-based study linking medical records and cancer registry data in Sweden, which revealed a relative risk over 10 for early CMV infection and the child’s hematologic malignancy diagnosis. We propose here to definitively assess the epidemiology of CMV and ALL including CMV’s impact on the ALL tumor genome. We hypothesize that nCMV will contribute to ALL incidence and create specific mutational signatures present in ALL tumor genomes known to be associated with viral and infectious etiologies. In our first aim, we will better define the role of nCMV infection as an ALL risk factor in a study with over 3800 cases and 4897 controls, accounting for other risk factors such as birthweight, birth order, mode of delivery, polygenic risk score for ALL and parental ages neonatal immune phenotype, as well as the role of maternal CMV infection status during pregnancy. We will also assess whether CMV contributes to the higher risk of ALL in Latinos compared to other groups. As a second aim, we will test 1,020 children for CMV involvement at birth and within their matched ALL tumor genomes collected at diagnosis. We will investigate the presence of the APOBEC and Recombinase Activating Gene (RAG), virally-associated mutational signatures, within tumors that were nCMV positive compared to those from children negative for the virus. This research will leverage exceptional resources, including archived newborn blood specimens and population- based childhood ALL cases and controls, and maternal blood specimens collected during mid-pregnancy. In addition, the proposed study benefits from a high fraction of Latinos in the study population who carry a disproportionate burden of childhood ALL, include advanced laboratory techniques to identify neonatal and maternal CMV infection that have been refined in our laboratory, and will evaluate directly a mutation signature putatively caused by the virus. CMV is a highly adept immune manipulator. Identification of CMV as an etiologic agent in childhood ALL could create an unprecedented target for leukemia prevention, either by vaccination against CMV infection or manipulation of the host response to CMV infection after birth. In either scenario, this proposal will better characterize the role of CMV in the genesis of childhood ALL and have profound impact from a prevention perspective. As CMV is also responsible for congenital hearing loss and a host of other neurological outcomes, our research will impact childhood health apart from leukemia.