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）中最常见的癌症。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， 预防是优先事项。缺乏可改变的病因学因素一直是预防的主要障碍，但我们 最近有一个突破性的发现（尽管是初步的），即新生儿巨细胞病毒（nCMV）感染 是儿童ALL的一个强危险因素（估计比值比= 3.7），在一项小型研究中，268例病例和270例 对照在同一研究中，我们还在治疗前诊断性肿瘤组织中发现了CMV序列。在 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， 结果显示，早期CMV感染和儿童血液恶性肿瘤的相对风险超过10， 诊断.我们建议明确评估CMV和ALL的流行病学，包括CMV的影响 在ALL肿瘤基因组上。我们假设nCMV将导致ALL的发生率，并产生特异性 已知与病毒和感染性疾病相关的ALL肿瘤基因组中存在的突变特征 病因学在我们的第一个目标中，我们将在一项研究中更好地定义nCMV感染作为ALL风险因素的作用， 超过3800例病例和4897例对照，占其他危险因素，如出生体重，出生顺序， 分娩、ALL多基因风险评分和父母年龄新生儿免疫表型，以及 孕妇在怀孕期间的CMV感染状况。我们还将评估CMV是否有助于更高的 与其他群体相比，拉丁美洲人的ALL风险。作为第二个目标，我们将对1,020名儿童进行CMV检测， 在出生时和诊断时收集的匹配ALL肿瘤基因组中的参与。我们将调查 APOBEC和腺苷酸酶激活基因（RAG）的存在，病毒相关突变， 在nCMV阳性的肿瘤中，与病毒阴性的儿童相比，这 研究将利用特殊的资源，包括存档的新生儿血液标本和人口- 基于儿童ALL病例和对照，以及在妊娠中期采集的母亲血液标本。在 此外，拟议的研究受益于研究人群中携带艾滋病毒的拉丁美洲人的高比例， 儿童ALL的不成比例的负担，包括先进的实验室技术，以确定新生儿和 我们的实验室已经完善了母体CMV感染，并将直接评估突变特征 病毒引起的脓疱CMV是一种非常熟练的免疫操纵者。鉴定CMV为 儿童ALL的病原体可能为白血病预防创造一个前所未有的目标， 接种抗CMV感染的疫苗或操纵出生后宿主对CMV感染的应答。在任一 该方案将更好地描述CMV在儿童ALL发生中的作用， 从预防的角度看，影响深远。由于巨细胞病毒也负责先天性听力损失和 除了白血病之外，我们的研究还将影响儿童健康。

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.