Molina-Pinelo Sonia, Salinas Ana, Moreno-Mata Nicolás, Ferrer Irene, Suarez Rocío, Andrés-León Eduardo, Rodríguez-Paredes Manuel, Gutekunst Julian, Jantus-Lewintre Eloisa, Camps Carlos, Carnero Amancio, Paz-Ares Luis
Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.
Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Oncotarget. 2016 Jul 15;9(4):4395-4410. doi: 10.18632/oncotarget.10611. eCollection 2018 Jan 12.
DNA methylation is important for gene expression and genome stability, and its disruption is thought to play a key role in the initiation and progression of cancer and other diseases. The cluster has been shown to be imprinted in humans, and some of its components are relevant to diverse pathological processes. The purpose of this study was to assess the methylation patterns of the cluster in patients with lung cancer to study its relevance in the pathogenesis of this disease. We found a characteristic methylation pattern of this cluster in smoking associated lung cancer, as compared to normal lung tissue. This methylation profile is not patent however in lung cancer of never smokers nor in lung tissue of COPD patients. We found 3 deregulated protein-coding genes at this locus: one was hypermethylated () and two were hypomethylated ( and ). Statistically significant differences were also detected in two different families of SNORDs, two miRNA clusters and four lncRNAs (, , and ). These findings were validated using data from the cancer genome atlas (TCGA) database. We have then showed an inverse correlation between DNA methylation and expression levels in 5 randomly selected genes. Several targets of miRNAs included in the cluster have been experimentally verified as tumor suppressors. All of these results suggest that the dysmethylation of the imprinted cluster could have a relevant role in the pathogenesis of lung cancer in current and former smokers and may be used for diagnostic and/or therapeutic purposes.
DNA甲基化对基因表达和基因组稳定性至关重要，其破坏被认为在癌症和其他疾病的发生发展中起关键作用。该基因簇已被证明在人类中存在印记，其一些组成部分与多种病理过程相关。本研究的目的是评估肺癌患者中该基因簇的甲基化模式，以研究其在该疾病发病机制中的相关性。与正常肺组织相比，我们在吸烟相关的肺癌中发现了该基因簇的特征性甲基化模式。然而，这种甲基化谱在从不吸烟者的肺癌中以及慢性阻塞性肺疾病（COPD）患者的肺组织中并不明显。我们在该位点发现了3个失调的蛋白质编码基因：一个发生了高甲基化（），两个发生了低甲基化（和）。在两个不同的小分子核仁RNA（SNORD）家族、两个微小RNA（miRNA）簇和四个长链非编码RNA（lncRNA）（、、和）中也检测到了统计学上的显著差异。这些发现使用来自癌症基因组图谱（TCGA）数据库的数据进行了验证。然后，我们在5个随机选择的基因中显示了DNA甲基化与表达水平之间的负相关。该基因簇中包含的几个miRNA的靶标已通过实验验证为肿瘤抑制因子。所有这些结果表明，印记基因簇的甲基化异常可能在当前和既往吸烟者肺癌的发病机制中起相关作用，并可用于诊断和/或治疗目的。
