Smigiel Robert, Stembalska-Kozlowska Agnieszka, Mirghomizadeh Farhad, Krecicki Tomasz, Zatonski Tomasz, Ramsey David, Horobiowska Monika, Jagielski Jozef, Blin Nikolaus, Sasiadek Maria
Department of Pathophysiology, Medical University of Wroclaw, 50-368 Wroclaw, Poland.
Oncol Rep. 2004 Mar;11(3):707-10.
Extensive molecular studies in development of the squamous cell carcinoma of larynx (SCCL) indicated the involvement of a variety of genes including the MLH1. To search for possible mechanism leading to MLH1 silencing in SCCL we studied LOH and promoter methylation in a homogeneous set of 62 larynx cancers. Then we evaluated immunohistochemically the MLH1 expression for 51 tumor specimens. Further, the results were correlated with microsatellite instability and subsequently with the clinical course of the disease. LOH at the MLH1 locus and aberrant methylation of its promoter were found in 47.9 and in 22.6% of tumors, respectively. A decreased expression was observed in 27.5% of the cases. MSI analysis of tumor DNA showed a microsatellite stable phenotype in 59 cases (95.2%). From our study it can be concluded that: i) molecular alterations of MLH1 play an important role in SSCL development, ii) both LOH and aberrant methylation contribute to the MLH1 inactivation in SCCL and are associated with a less advanced stage of differentiation of larynx tumors, iii) MLH1 inactivation does not lead to MSI in larynx cancer and MSI may not contribute to the development of SCCL.
对喉鳞状细胞癌（SCCL）发生发展的广泛分子研究表明，多种基因参与其中，包括MLH1。为了探寻导致SCCL中MLH1沉默的可能机制，我们对62例喉癌的同质样本进行了杂合性缺失（LOH）和启动子甲基化研究。然后，我们对51个肿瘤标本进行了MLH1表达的免疫组织化学评估。此外，将结果与微卫星不稳定性相关联，并随后与疾病的临床进程相关联。在47.9%的肿瘤中发现了MLH1基因座的LOH，其启动子的异常甲基化发生率为22.6%。在27.5%的病例中观察到表达降低。对肿瘤DNA的微卫星不稳定性（MSI）分析显示，59例（95.2%）呈现微卫星稳定表型。从我们的研究可以得出以下结论：i）MLH1的分子改变在SCCL的发生发展中起重要作用；ii）LOH和异常甲基化均导致SCCL中MLH1失活，并与喉肿瘤分化程度较低的阶段相关；iii）MLH1失活不会导致喉癌中的MSI，且MSI可能对SCCL的发生发展没有作用。
