Murao K, Kubo Y, Ohtani N, Hara E, Arase S
Department of Dermatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Br J Dermatol. 2006 Nov;155(5):999-1005. doi: 10.1111/j.1365-2133.2006.07487.x.
Aberrant methylation of CpG islands in the promoter regions of cancer-related genes has been demonstrated in many human tumours. However, the methylation profile of these regions in cutaneous squamous cell carcinomas (SCCs) has not been well studied.
To examine epigenetic abnormalities of a wide range of cancer-related genes in SCCs.
We investigated the methylation status of 11 candidate cancer-related genes (CDH1, p16(INK4a), p14(ARF), DAPK1, MGMT, RB1, RASSF1, p15(INK4b), PTEN, PRDM2 and p53) in 20 cases of SCC by methylation-specific polymerase chain reaction, and comparatively examined the protein production of E-cadherin (CDH1), p16, RB1, p14, BMI1 and cyclin A by immunohistochemical analysis.
The frequency of cancer-related gene methylation in SCCs was: CDH1 (95%), p16 (20%), p14 (15%), DAPK1 (15%), MGMT (15%), RB1 (5%), RASSF1 (5%), p15 (0%), PTEN (0%), PRDM2 (0%) and p53 (0%). Almost all cases with hypermethylation of CDH1, p16, RB1 and p14 showed no obvious production of each protein, suggesting that promoter hypermethylation of these genes contributes to the loss of protein production. The results of methylation analysis, in combination with the results of our previous mutation analysis of CDKN2A locus and p53, revealed that 70% of SCCs have alterations in the RB1/p16 or p53 pathway.
Our findings indicate that the promoter hypermethylation of cancer-related genes, especially CDH1, is frequently shown in SCCs, and dysregulation of the RB1/p16 and/or p53 pathway through either genetic or epigenetic mechanisms, except for epigenetic abnormalities of p53 itself, should contribute to the carcinogenesis of SCCs.
癌症相关基因启动子区域CpG岛的异常甲基化已在许多人类肿瘤中得到证实。然而，皮肤鳞状细胞癌（SCC）中这些区域的甲基化谱尚未得到充分研究。
研究SCC中广泛的癌症相关基因的表观遗传异常。
我们通过甲基化特异性聚合酶链反应研究了20例SCC中11个候选癌症相关基因（CDH1、p16(INK4a)、p14(ARF)、DAPK1、MGMT、RB1、RASSF1、p15(INK4b)、PTEN、PRDM2和p53）的甲基化状态，并通过免疫组织化学分析比较检测了E-钙黏蛋白（CDH1）、p16、RB1、p14、BMI1和细胞周期蛋白A的蛋白表达。
SCC中癌症相关基因甲基化的频率为：CDH1（95%）、p16（20%）、p14（15%）、DAPK1（15%）、MGMT（15%）、RB1（5%）、RASSF1（5%）、p15（0%）、PTEN（0%）、PRDM2（0%）和p53（0%）。几乎所有CDH1、p16、RB1和p14高甲基化的病例均未显示出各蛋白的明显表达，这表明这些基因的启动子高甲基化导致了蛋白表达的缺失。甲基化分析结果与我们之前对CDKN2A基因座和p53的突变分析结果相结合，显示70%的SCC在RB1/p16或p53途径存在改变。
我们的研究结果表明，癌症相关基因的启动子高甲基化，尤其是CDH1，在SCC中经常出现，并且除了p53自身的表观遗传异常外，通过遗传或表观遗传机制导致的RB1/p16和/或p53途径失调应有助于SCC的致癌过程。
