Sasiadek M M, Stembalska-Kozlowska A, Smigiel R, Ramsey D, Kayademir T, Blin N
Department of Genetics, Medical University, ul. Marcinkowskiego 1, Wroclaw 50-368, Poland.
Br J Cancer. 2004 Apr 19;90(8):1594-9. doi: 10.1038/sj.bjc.6601679.
Our study aimed at elucidating which genetic alterations tend to form a network and could be applied as molecular markers of larynx squamous cell carcinoma (LSCC). A panel of genes involved in tumorigenesis was investigated. To search for the possible mechanisms of gene silencing, loss of heterozygosity (LOH) was analysed followed by testing DNA methylation and protein expression for those genes found with the highest frequency of LOH (CDKN2A (55.4%), MLH1 (46.0%), RB1 (35.7%)). A correlation of both LOH and hypermethylation with the loss of expression for CDKN2A and MLH1 was found. Disrupted Rb pathway (loss of expression of RB1 and/or of CDKN2A) in 55.9% of analysed cases confirmed the hypothesis that RB1 pathway is altered in head and neck squamous cell carcinomas, with CDKN2A (45%), rather than RB1 (11.8%) being more frequently inactivated. In LSCC, LOH tends to occur together in gene pairs or triplets. The pair MLH1/CDKN2A and triplets MLH1/TSG on 8p22/CDKN2A and MLH1/CDKN2A/RB1 are related to staging and grading. LOH in MLH1 correlates with lower and LOH in CDKN2A with higher grades of LSCC. It can be concluded that MLH1 and CDKN2A play an important role in LSCC development and progression.
我们的研究旨在阐明哪些基因改变倾向于形成一个网络，并可作为喉鳞状细胞癌（LSCC）的分子标志物。对一组参与肿瘤发生的基因进行了研究。为了寻找基因沉默的可能机制，分析了杂合性缺失（LOH），随后对那些LOH频率最高的基因（CDKN2A（55.4%）、MLH1（46.0%）、RB1（35.7%））进行DNA甲基化和蛋白质表达检测。发现LOH和高甲基化均与CDKN2A和MLH1的表达缺失相关。在55.9%的分析病例中，Rb通路中断（RB1和/或CDKN2A表达缺失）证实了头颈部鳞状细胞癌中RB1通路发生改变的假设，其中CDKN2A（45%）比RB1（11.8%）更频繁地失活。在LSCC中，LOH倾向于在基因对或三联体中共同出现。MLH1/CDKN2A对以及8p22上的MLH1/TSG/CDKN2A三联体和MLH1/CDKN2A/RB1三联体与分期和分级相关。MLH1中的LOH与较低分期相关，而CDKN2A中的LOH与较高分级的LSCC相关。可以得出结论，MLH1和CDKN2A在LSCC的发生和发展中起重要作用。
