Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation. Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.

中文翻译：

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小儿急性淋巴细胞白血病发展跨度的表观全基因组分析：追溯至出生


癌症是儿童疾病相关死亡的主要原因。白血病是最常见的白血病，其病因在很大程度上是未知的。越来越多的证据表明，子宫内起源，当 DNA 甲基化发生全局重新分布时，驱动组织分化。在儿科 pre-B 急性淋巴细胞白血病 （pre-B ALL） 患者出生、诊断、缓解和复发时，在替代 （血液） 和靶 （骨髓） 组织中分析表观全基因组 DNA 甲基化。在从出生到诊断的前瞻性队列和从临床疾病追溯到出生的回顾性研究之间进行双盲分析。使用独立的技术和人群进行验证。在所有测试人群 （总计 317 例和 483 例对照） 中，包括欧洲和西班牙裔血统的巢病例相比，印迹和免疫调节 VTRNA2-1 在出生时被高甲基化 （FDR<0.05）。VTRNA2-1 甲基化在出生后几年的随访中以及跨替代组织、靶组织和其他组织 （n=5,023 个组织;30 种类型） 保持稳定。当在两个临床队列 （共 644 例） 的白血病组织中进行分析时，VTRNA2-1 甲基化在诊断时相对于对照组表现出更高的水平，它在缓解时重置回正常水平，然后在复发时重新增加到高于对照水平。高甲基化与 B 前 ALL 患者生存率较差和 VTRNA2-1 表达降低 （n=2,294 个组织;26 种类型） 显著相关，支持 VTRNA2-1 甲基化的功能和翻译作用。本研究为检测儿科前 B ALL 的出生表观遗传前体提供了概念验证。 这些改变可以在三大洲和两个种族的不同技术中重现，并且可以为早期检测和预后提供生物标志物以及可操作的治疗靶点。• 小儿急性淋巴细胞白血病的前体可能起源于表观遗传，自出生起即可检测到并影响患者的预后。• 这些表观遗传前体可以在数年内以及多个人群、种族以及替代和靶组织中保持稳健。