Liu Zeyi, Zhao Jun, Chen Xiao-Feng, Li Wenwen, Liu Rengyun, Lei Zhe, Liu Xia, Peng Xiaobei, Xu Ke, Chen Jun, Liu Hongyu, Zhou Qing-Hua, Zhang Hong-Tao
Laboratory of Medical Genetics, School of Basic Medicine & Biological Sciences, Suzhou University, 199 Ren'ai Road, Sino-Singapore Industrial Park, 215123 Suzhou, PR China.
Lung Cancer. 2008 Oct;62(1):15-22. doi: 10.1016/j.lungcan.2008.02.005. Epub 2008 Mar 20.
CpG island methylator phenotype (CIMP) involving methylation abnormalities of tumor suppressor gene (TSG) on short arm of chromosome 3 (chromosome 3p) has not been so far epigenetically elucidated in non-small cell lung cancer (NSCLC). Using methylation-specific PCR (MSP) method, we examined methylation profiles for eight TSGs harbored in chromosome 3p in 60 NSCLC tissues and 60 paired normal tissues as well as 11 normal blood samples. CIMP positive is referred to having four or more than four synchronously methylated genes per sample. Consequently, 59 of 60 (98.3%) NSCLC presented promoter methylation of at least one gene while only one malignant tumor showed no methylation of any of eight genes. The frequency of promoter methylation for eight genes explored ranged from 12% for hMLH1 to 67% for RASSF1A given that of VHL (none) was not considered. Interestingly, CIMP+ was found in 56.7% (34/60) of NSCLC, and in 6.7% (4/60) of paired normal tissues and 0% (0/11) of normal blood samples, respectively; CIMP- was present in 43.3% (26/60) of NSCLC, 93.3% (56/60) of paired normal tissues, and 100% (11/11) of normal blood samples, respectively. The data suggest that CIMP status was significantly associated with NSCLC, paired normal tissues and normal blood samples (P<0.001). In addition, there appeared to be a significant association between CIMP status and survival prognosis of NSCLC (P=0.0166). In the present study, for the first time, we shed light on the presence of chromosome 3p-specific CIMP, which might play an important role in tumorigenesis of NSCLC.
涉及3号染色体短臂（3p染色体）上肿瘤抑制基因（TSG）甲基化异常的CpG岛甲基化表型（CIMP），在非小细胞肺癌（NSCLC）中尚未得到表观遗传学方面的阐明。我们使用甲基化特异性PCR（MSP）方法，检测了60例NSCLC组织、60例配对的正常组织以及11份正常血液样本中3p染色体上8个TSG的甲基化谱。CIMP阳性是指每个样本中有4个或4个以上基因同步甲基化。结果显示，60例NSCLC中有59例（98.3%）至少有一个基因的启动子甲基化，而只有一个恶性肿瘤的8个基因均未发生甲基化。在所研究的8个基因中，hMLH1的启动子甲基化频率为12%，RASSF1A为67%（未考虑VHL的甲基化频率，其为0）。有趣的是，NSCLC中56.7%（34/60）为CIMP阳性，配对正常组织中为6.7%（4/60），正常血液样本中为0%（0/11）；NSCLC中43.3%（26/60）为CIMP阴性，配对正常组织中为93.3%（56/60），正常血液样本中为100%（11/11）。数据表明，CIMP状态与NSCLC、配对正常组织及正常血液样本显著相关（P<0.001）。此外，CIMP状态与NSCLC的生存预后之间似乎也存在显著关联（P=0.0166）。在本研究中，我们首次揭示了3p染色体特异性CIMP的存在，其可能在NSCLC的肿瘤发生中起重要作用。
