Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France.
Genknowme SA, Alanine Building, Corniche Road 5, 1066, Epalinges, Switzerland.
Mol Cancer. 2024 Oct 23;23(1):238. doi: 10.1186/s12943-024-02118-4.
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.
癌症是导致儿童死亡的主要疾病原因。白血病是最常见的一种，其发病原因在很大程度上尚不清楚。越来越多的证据表明，白血病起源于子宫内，此时 DNA 甲基化会发生全局再分配，从而驱动组织分化。
在患有儿童前 B 急性淋巴细胞白血病（pre-B ALL）的患者出生、诊断、缓解和复发时，对其替代（血液）和目标（骨髓）组织进行全基因组 DNA 甲基化谱分析。在从出生到诊断的前瞻性队列和从临床疾病回溯到出生的回顾性研究之间进行了双盲分析。使用独立的技术和人群进行了验证。
在所测试的所有人群（共 317 例病例和 483 例对照）中，包括欧洲和西班牙裔血统，与对照组相比，印迹和免疫调节的 VTRNA2-1 在嵌套病例中出生时就呈超甲基化（FDR<0.05）。VTRNA2-1 甲基化在出生后多年的随访中以及在替代物、目标物和其他组织（n=5023 个组织；30 种类型）中都很稳定。当在两个临床队列（共 644 例病例）的白血病组织中进行分析时，VTRNA2-1 甲基化在诊断时相对对照病例升高，在缓解时恢复正常水平，然后在复发时再次升高至高于对照水平。高甲基化与较差的 pre-B ALL 患者生存和 VTRNA2-1 表达减少显著相关（n=2294 个组织；26 种类型），支持 VTRNA2-1 甲基化的功能和转化作用。
本研究提供了在出生时检测儿科 pre-B ALL 表观遗传前体的概念验证。这些改变可以通过不同的技术、在三大洲和两种种族中重现，并且可以提供早期检测和预后的生物标志物，以及治疗的作用靶点。
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