Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23-25
Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23-25
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DOI：
10.1158/0008-5472.can-07-6325
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Belinsky, Steven A.
中科院分区：
文献类型：
--
作者：
Tessema, Mathewos;Willink, Randy;Belinsky, Steven A.
与肺癌相关的染色体畸变经常在6号染色体长臂上观察到。最近发现6 q23 -25是肺癌的一个候选易感灶，但在该易感灶中尚未发现因突变而失活的抑癌基因。使用遗传、表观遗传、基因表达和计算机模拟筛选方法选择位于6 q12 -27的43个基因用于甲基化状态的表征。12个（28%）基因在至少一个肺癌细胞系中发生甲基化，其中8个基因的甲基化是肺癌细胞系特异性的。在来自吸烟者（n = 100）和从不吸烟者（n = 75）的原发性肺腺癌样品中检查了在细胞系中具有最高甲基化流行率的8个基因中的5个（TCF 21、SYNE 1、AKAP 12、IL 20 RA和ACAT 2）。这些基因甲基化的患病率分别为81%、50%、39%、26%和14%，并且在诊断时吸烟状况或年龄方面没有差异。SYNE 1、AKAP 12和IL 20 RA的转录被高甲基化完全沉默，并且在用5-氮杂-2-脱氧胞苷处理后可以恢复。SYAE 1和TCF 21，SYNE 1和AKAP 12，AKAP 12和IL 20 RA的甲基化之间存在显著相关性，表明这些基因在肿瘤中协同失活。这些基因甲基化的高患病率与早发性肺癌病例无关，很可能排除了他们参与这种疾病的家族易感性。总之，我们的研究结果表明，染色体6 q内多个候选肿瘤抑制基因的频繁失活可能有助于散发性肺癌的发展。
Chromosomal aberrations associated with lung cancer are frequently observed in the long arm of chromosome 6. A candidate susceptibility focus at 6q23-25 for lung cancer was recently identified; however, no tumor suppressor genes inactivated by mutation have been identified in this focus. Genetic, epigenetic, gene expression, and in silico, screening approaches were used to select 43 genes located in 6q12-27 for characterization of methylation status. Twelve (28%) genes were methylated in at least one lung cancer cell line, and methylation of 8 genes was specific to lung cancer cell lines. Five of the 8 genes with the highest prevalence for methylation in cell lines (TCF21, SYNE1, AKAP12 IL20RA, and ACAT2) were examined in primary lung adenocarcinoma samples from smokers (n = 100) and never smokers (n = 75). The prevalence for methylation of these genes was 81%, 50%, 39%, 26%, and 14%, respectively, and did not differ by smoking status or age at diagnosis. Transcription of SYNE1, AKAP12, and IL20RA was completely silenced by hypermethylation and could be restored after treatment with 5-aza-2-deoxycytidine. Significant associations were found between methylation of SYAE1 and TCF21, SYNE1 and AKAP12, and AKAP12 and IL20RA, indicating a coordinated inactivation of these genes in tumors. A higher prevalence for methylation of these genes was not associated with early-onset lung cancer cases, most likely precluding their involvement in familial susceptibility to this disease. Together, our results indicate that frequent inactivation of multiple candidate tumor suppressor genes within chromosome 6q likely contributes to development of sporadic lung cancer.