Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T-Cell Leukemia/Lymphoma
Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T-Cell Leukemia/Lymphoma
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DOI：
10.2353/ajpath.2010.090236
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发表时间：
2010-01-01
影响因子：
6
通讯作者：
Yoshino, Tadashi
中科院分区：
文献类型：
--
作者：
Sato, Hiaki;Oka, Takashi;Yoshino, Tadashi
异常的 CpG 岛甲基化有助于各种恶性肿瘤的发病机制。然而，人们对表观遗传异常与成人 T 细胞白血病/淋巴瘤 (ATLL) 多步致瘤事件的关联知之甚少。为了确定表观遗传异常是否会导致 ATLL 的进展，我们通过甲基化特异性 PCR 检测对 65 例 ATLL 患者的 SHP1、p15、p16、p73、HCAD、DAPK、hMLH-1 和 MGMT 基因的甲基化谱进行了分析。 CpG 岛甲基化基因的数量随着疾病进展而增加，甚至在 HTLV-1 携带者中也检测到特定基因的异常高甲基化，并且与 ATLL 的进展相关。 CpG岛甲基化表型（CIMP）在淋巴瘤型ATLL中最常见，并且与ATLL的进展和危象密切相关。 Kaplan-Meyer 分析表明，大量甲基化基因和 CIMP 发生率增加是不利的预后因素，并且与较短的总生存期相关。目前的研究结果强烈表明，特定靶基因中异常 CpG 甲基化的多步积累和 CIMP 的存在与 ATLL 的危机、进展和预后密切相关，并表明 CpG 甲基化和 CIMP 对于新的诊断和预后生物标志物的价值。 （Am J Pathol 2010，176：402-415；DOI：10.2353/ajpath.2010.090236）
Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers. (Am J Pathol 2010, 176:402-415; DOI: 10.2353/ajpath.2010.090236)