Congenital cytomegalovirus infection, KIR genotypes, and acute lymphoblastic leukemia

摘要 急性淋巴细胞性白血病(ALL)是最常见的儿科癌症，也是导致死亡的主要原因 在孩子们身上。与普通人群相比，所有幸存者都面临着巨大的终身健康风险。 因此，了解儿童ALL的病因，以便及早发现和预防是一项 这是改善儿童和成人健康的重要目标。最近一份具有挑衅性的报告暗示， 新生儿样本中ALL与巨细胞病毒(CMV)产前感染的相关性 来自加州268例ALL患者和270名对照的干血斑(DBS)。在DBS中检出CMV 26/248 病例(9.7%)，但只有8/270(3%)的对照，优势比(OR)为3.71(95%可信区间 区间(CI)：1.71~8.95。这就提出了一个重要的问题，即潜在的产前巨细胞病毒感染 有助于儿科ALL的发展。在一项大规模的基于人群的研究中重复了这一发现 这是正当的。先天免疫是控制感染和监测白血病前期克隆的关键因素。 这种免疫监视的中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细胞上特异表达，KIR与HLA的相互作用决定了NK细胞的表型 (插入评论)。先天免疫的这一重要因素与感染的易感性有关， 包括巨细胞病毒在怀孕期间的重新激活和传播。然而，关于这一角色，有相互矛盾的报道 KIR-HLA在儿童ALL中的应用到目前为止，还没有研究同时考虑CMV和 先天免疫中的这些功能性遗传变异。确认先天性巨细胞病毒感染与 为了阐明KIR-HLA在儿童ALL中的作用，我们建议对1158名儿童进行一项基于人群的研究 从密歇根生物信托基金会获得的病例和对照在性别、种族/民族和出生年份方面匹配4：1 健康。两个病例和对照在出生时获得的干血斑(DB)将被检测CMV，KIR 单倍型和先前在全基因组关联研究中发现的已知风险变异。作为细胞遗传学 亚型不是由密歇根州癌症登记处常规收集的，我们将从六个 该州治疗儿科肿瘤患者的机构。我们的具体目标是：(1)比较CMV 所有病例新生儿DBS的出生时患病率与对照组比较(2)KIR-HL A基因分型比较 病例和对照。此外，我们还有两个探索性的目的：(1)检测KIR-人类白细胞抗原(KIR-HL A)的遗传学改变 先天性巨细胞病毒感染与急性淋巴细胞白血病的关联以及(2)描述KIR-HLA变异的关联 出生时有巨细胞病毒感染。证实先天性巨细胞病毒感染与 ALL的发展将首次为最常见的 儿童癌症，以及增加了正在进行的检测和减轻先天性癌症影响的努力的紧迫性 巨细胞病毒感染。

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.