Congenital cytomegalovirus infection, KIR genotypes, and acute lymphoblastic leukemia

先天性巨细胞病毒感染、KIR 基因型和急性淋巴细胞白血病

• 批准号: 9897463
• 负责人: HEATHER Hammond NELSON
• 金额: $ 40.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897463
• 关键词: Acute Lymphocytic Leukemia; Adult; Bacteria; Biological Assay; Biological Markers; Birth; Blood; CEBPE gene; California; Cancer Etiology; Cause of Death; Cell Communication; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Confidence Intervals; Conflict (Psychology); Country; Cytogenetic Analysis; Cytogenetics; Cytomegalovirus; Cytomegalovirus Infections; Development; Disease; Early Diagnosis; Elements; Ethnic Origin; Etiology; Exposure to; General Population; Genes; Genetic; Genome; Genotype; Goals; Haplotypes; Health; Immunologic Surveillance; Infection; Infection Control; Institution; Investigation; Leukemic Cell; Ligands; Literature; Logistic Regressions; Malignant Childhood Neoplasm; Michigan; Modification; Molecular; Natural Immunity; Natural Killer Cells; Newborn Infant; Odds Ratio; Outcome; Patients; Pediatric Oncology; Perinatal; Phenotype; Population; Population Study; Predisposition; Pregnancy; Prevalence; Prevention; Proxy; Race; Recording of previous events; Reporting; Risk; Risk Factors; Role; Sampling; Spottings; Survivors; Testing; Time; United States; Variant; Viral; Virus; adult leukemia; base; case control; congenital cytomegalovirus; digital; disorder risk; experience; genetic variant; genome wide association study; immunoglobulin receptor; improved; modifiable risk; neoplasm registry; population based; prenatal; public health relevance; risk variant; sex; transmission process

Abstract Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Survivors of ALL experience substantial lifelong health risks compared to the general population. Understanding the causes of pediatric ALL in order to enable its early detection and prevention is therefore an important goal for improving both pediatric and adult health. A provocative recent report suggested an association of ALL with prenatal infection with cytomegalovirus (CMV) in a population-based sample of newborn dried blood spots (DBS) from 268 ALL cases and 270 controls in California. CMV was detected in DBS of 26/248 (9.7%) of case but only 8/270 (3%) of controls for a highly significant odds ratio (OR) of 3.71 (95% Confidence Interval (CI): 1.71-8.95). This raises the important question as to whether subclinical prenatal CMV infection contributes to the development of pediatric ALL. Replication of this finding in a large population-based study is warranted. Innate immunity is a key factor in both the control of infection and surveillance of pre-leukemic clones. Central to this immune surveillance are high functioning Natural Killer (NK) cells. Killer Immunoglobulin Receptors (KIR) are specifically expressed on NK cells, and interaction between KIR and HLA dictates NK cell phenotype (insert review). This important element of innate immunity has been associated with susceptibility to infections, including CMV reactivation and transmission in pregnancy. However, there are conflicting reports on the role of KIR-HLA in pediatric ALL and to date there have been no studies that have simultaneously considered CMV and these functional genetic variants in innate immunity. To confirm an association of congenital CMV infection and ALL and to clarify the role of KIR-HLA in pediatric ALL, we propose to conduct a population-based study of 1158 cases and controls matched 4:1 on sex, race/ethnicity, and year of birth obtained from the Michigan BioTrust for Health. Dried blood spots (DBS) obtained at birth from both cases and controls will be assayed for CMV, KIR haplotypes, and known risk variants previously discovered in genomewide association studies. As cytogenetic subtype is not routinely collected by the Michigan cancer registry, we will obtain this information from six institutions in the state that treat pediatric oncology patients. Our specific aims are to: (1) Compare CMV prevalence at birth in newborn DBS of ALL cases to that in controls and (2) Compare KIR-HLA genotypes among cases and controls. In addition we have two exploratory aims to: (1) Examine whether KIR-HLA genetics modify the association between congenital CMV infection and ALL and (2) Describe the association of KIR-HLA variants with CMV prevalence at birth. Confirmation of an association between congenital CMV infection and development of ALL will for the first time establish a potentially modifiable risk factor for the most common childhood cancer, as well as adding urgency to ongoing efforts to detect and mitigate the effects of congenital CMV infection.

摘要 急性淋巴细胞白血病（ALL）是最常见的儿科癌症，也是导致死亡的主要原因 小儿与一般人群相比，ALL的幸存者经历了重大的终身健康风险。 因此，了解儿童ALL的原因，以便能够早期发现和预防， 改善儿童和成人健康的重要目标。最近一份挑衅性的报告显示， 基于人群的新生儿样本中ALL与产前巨细胞病毒（CMV）感染的关系 来自加州的268例ALL病例和270例对照的干血斑（DBS）。26/248例DBS检出CMV (9.7而对照组仅为8/270（3%），具有高度显著性优势比（OR）为3.71（95%置信度 区间（CI）：1.71-8.95）。这就提出了一个重要的问题，即亚临床产前CMV感染是否 有助于儿童ALL的发展。在一项大规模人群研究中重复这一发现， 有正当理由先天免疫是控制感染和监测白血病前克隆的关键因素。 这种免疫监视的核心是高功能的自然杀伤（NK）细胞。杀伤免疫球蛋白受体 (KIR)在NK细胞上特异性表达，KIR和HLA之间的相互作用决定了NK细胞表型 （插入审查）。这种先天免疫的重要元素与感染的易感性有关， 包括妊娠期CMV再激活和传播。然而，关于联合国的作用， 儿童ALL中的KIR-HLA，迄今为止，还没有同时考虑CMV和 这些先天免疫中的功能性遗传变异。确认先天性CMV感染与 为了阐明KIR-HLA在儿童ALL中的作用，我们建议对1158例儿童ALL患者进行一项基于人群的研究。 病例和对照组在性别、种族/民族和出生年份上匹配4：1，这些数据来自密歇根生物信托基金会， 健康将对出生时从病例和对照组中获得的干血斑（DBS）进行CMV、KIR检测 单倍型和已知的风险变异先前发现的全基因组关联研究。作为细胞遗传学 密歇根州癌症登记处不定期收集亚型，我们将从六个 治疗儿科肿瘤患者的机构。我们的具体目标是：（1）比较CMV ALL患者与对照组新生儿DBS的出生时患病率;（2）比较ALL患者与对照组之间KIR-HLA基因型的差异。 病例和对照。此外，我们还有两个探索性的目的：（1）检测KIR-HLA基因是否修饰了 先天性CMV感染与ALL之间的关联;（2）描述KIR-HLA变异体之间的关联 与出生时巨细胞病毒感染率有关。确认先天性CMV感染与 ALL的发展将首次建立一个潜在的可改变的风险因素， 儿童癌症，并增加了正在进行的努力，以检测和减轻先天性癌症的影响的紧迫性， CMV感染。