Hematopathology Section, Department of Anatomic Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
PLoS One. 2011;6(5):e19736. doi: 10.1371/journal.pone.0019736. Epub 2011 May 16.
Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance.
METHODOLOGY/PRINCIPAL FINDINGS: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients.
We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.
套细胞淋巴瘤（MCL）在遗传学上的特征是 t（11；14）（q13；q32）易位和大量的次级染色体改变。DNA 甲基化在 MCL 肿瘤发生中的作用尚不清楚。我们试图确定这些肿瘤中存在的表观遗传沉默基因，这些基因可能具有临床相关性。
方法/主要发现：为了鉴定 MCL 中的潜在甲基化基因，我们最初研究了 7 种用表观遗传学药物处理的 MCL 细胞系，并进行了基因表达微阵列分析。通过定量测定验证了选定候选基因的甲基化状态，随后在一系列原发性 MCL 中进行了分析（n=38）。在药物逆转后，我们鉴定出 252 个潜在的甲基化基因。对这些基因的一个亚组（n=25）在 MCL 细胞系和正常 B 淋巴细胞中的甲基化分析证实，其中 80%的基因在细胞系中甲基化，但在正常淋巴细胞中不甲基化。随后在原发性 MCL 中的分析确定了五个基因（SOX9、HOXA9、AHR、NR2F2 和 ROBO1）在这些肿瘤中经常甲基化。基因甲基化事件往往发生在相同的原发性肿瘤中，并与更高的增殖、更多的染色体异常以及患者的生存时间缩短相关。
我们已经确定了一组基因，其甲基化程度和基因表达水平与 MCL 的侵袭性临床病理特征相关。我们的研究结果还表明，一部分 MCL 可能表现出 CpG 岛甲基化表型（CIMP），这可能影响肿瘤的行为。
