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

巨细胞病毒作为儿童急性淋巴细胞白血病的病因和临床致病因素

• 批准号: 10391271
• 负责人: Xiaomei Ma
• 金额: $ 70.34万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391271
• 关键词: ARG2 gene; Accounting; Acute Lymphocytic Leukemia; Affect; Age; Archives; Attention; Birth; Birth Order; Blood specimen; Bone Marrow; Cells; Cesarean section; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Confidence Intervals; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Data; Defect; Diagnosis; Epidemiology; Ethnic Origin; Ethnic group; Etiology; Face; Female of child bearing age; Genes; Genetic Predisposition to Disease; Genome; Goals; Health; Hematologic Neoplasms; High Prevalence; High birth weight infant; Immune; Immune response; Immune system; Immunologic Markers; Incidence; Infection; Infection Control; Intervention; Laboratories; Latino; Latino Population; Life; Light; Link; Malignant Childhood Neoplasm; Measures; Mediating; Medical Records; Mental Retardation; Microcephaly; Mutation; Natural History; Neonatal; Neurological outcome; Newborn Infant; Odds Ratio; Outcome; Parental Ages; Pattern; Phenotype; Point Mutation; Population Study; Pregnancy; Pregnant Women; Prevention; Public Health; Relative Risks; Research; Resources; Risk; Risk Factors; Role; Sensorineural Hearing Loss; Seroprevalences; Somatic Mutation; Survivors; Sweden; Techniques; Testing; Tumor Tissue; United States; Vaccination; Viral; Virulence Factors; Virus; Virus Diseases; cancer genome; cancer type; case control; congenital hearing loss; cytokine; data registry; epidemiology study; high risk; immunoregulation; in utero; innovation; intrauterine infection; leukemia; leukemogenesis; neoplasm registry; non-genetic; novel; polygenic risk score; population based; prevent; racial and ethnic; recombinase; study population; treatment effect; tumor; tumor diagnostic

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.

抽象的 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，幸存者面临着终生与治疗的负面健康影响作斗争，使得 预防为主。缺乏可改变的病因一直是预防的主要障碍，但我们 最近做出了一项突破性的（尽管是初步的）发现，新生儿巨细胞病毒（nCMV）感染 在一项包含 268 例和 270 例的小型研究中，这是儿童 ALL 的一个强烈危险因素（估计比值比 = 3.7） 控制。在同一项研究中，我们还在治疗前的诊断性肿瘤组织中发现了 CMV 序列。在 此外，我们在瑞典进行了一项基于人群的研究，将医疗记录和癌症登记数据联系起来， 结果显示，早期 CMV 感染和儿童患血液系统恶性肿瘤的相对风险超过 10 诊断。我们在此建议明确评估 CMV 和 ALL 的流行病学，包括 CMV 的影响 在所有肿瘤基因组上。我们假设 nCMV 将导致 ALL 的发生并产生特定的 已知与病毒和传染性相关的所有肿瘤基因组中存在突变特征 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 危险因素的作用 超过 3800 例病例和 4897 例对照，考虑了其他风险因素，如出生体重、出生顺序、出生方式 分娩、ALL 的多基因风险评分和父母年龄新生儿免疫表型，以及 母亲怀孕期间巨细胞病毒感染状况。我们还将评估 CMV 是否有助于提高 与其他群体相比，拉丁美洲人患 ALL 的风险。第二个目标是，我们将对 1,020 名儿童进行 CMV 检测 出生时的参与以及诊断时收集的匹配的所有肿瘤基因组中的参与。我们将调查 APOBEC 和重组酶激活基因 (RAG) 的存在、病毒相关突变 与病毒阴性儿童的肿瘤相比，nCMV 呈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样本 基于儿童 ALL 病例和对照，以及怀孕中期收集的母体血液样本。在 此外，拟议的研究受益于研究人群中大部分拉丁裔人携带 儿童 ALL 的负担不成比例，包括先进的实验室技术来识别新生儿和 母体 CMV 感染已在我们的实验室中进行了改进，并将直接评估突变特征 推测是由病毒引起的。 CMV 是一种高度熟练的免疫操纵者。 CMV 的鉴定 儿童 ALL 的病因可以为白血病预防创造一个前所未有的目标，方法是： 针对 CMV 感染的疫苗接种或控制出生后宿主对 CMV 感染的反应。在任一 在这种情况下，该提案将更好地描述 CMV 在儿童 ALL 发生中的作用，并具有 从预防的角度来看，影响深远。由于 CMV 还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许多其他神经系统疾病的儿童健康。