Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer.

Both genetic and epigenetic changes in nonsmall cell lung cancer (NSCLC) are known to be a common event. Mutations in the epidermal growth factor receptor gene (EGFR), HER-2, and KRAS and the methylation profile of 9 genes for NSCLC were analyzed and correlated with clinical and histologic data. Thirty-nine EGFR, 4 HER-2, and 6 KRAS mutations were found in 150 NSCLC cases, with the methylation percentages of the genes ranging from 13% to 54%. Most mutations were present in adenocarcinomas, but mutations of the 3 genes were never found to be present in individual tumors. The frequency of methylation for all the genes was correlated with the Methylation Index, a reflection of the overall methylation pattern (all genes, P< or = .01), supporting the presence of the CpG island methylator phenotype (CIMP) in NSCLC. On the basis of the methylation profile, CRBP1 and CDH13 methylation were good indicators of CIMP in NSCLC, and were correlated with a poorer prognosis in adenocarcinomas. Mutations in EGFR, HER-2, and KRAS were found to be present exclusively, whereas methylation tended to be present synchronously. A comparison of mutation and methylation demonstrated that the EGFR mutation had an inverse correlation with methylation of SPARC (secreted protein acidic and rich in cysteine), an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16INK4A gene. The findings of the current study suggest that adenocarcinoma cases with CIMP have a poorer prognosis than adenocarcinoma cases without CIMP, and the EGFR mutation was shown to have an inverse correlation with methylation of SPARC and the p16INK4A gene in NSCLC.

Suzuki M ，Shigematsu H ，Iizasa T ，Hiroshima K ，Nakatani Y ，Minna JD ，Gazdar AF ，Fujisawa T ... -  《CANCER》

The methylation status and protein expression of CDH1, p16(INK4A), and fragile histidine triad in nonsmall cell lung carcinoma: epigenetic silencing, clinical features, and prognostic significance.

Aberrant methylation of the promoter CpG island (methylation) is known as a major inactivation mechanism of tumor suppressor and tumor-related genes. In this study, the authors studied the presence of methylation by investigated the inactivation of genes and prognostic factors in patients with nonsmall cell lung carcinoma (NSCLC) by examining resection samples for the presence of methylation. Samples were obtained from 224 patients who underwent pulmonary resection for NSCLC. The authors used those samples to study methylation status with methylation-specific polymerase chain reaction analysis and to study protein expression with immunohistochemistry for 3 different genes: CDH1, p16INK4A, and fragile histidine triad (FHIT). The frequency of methylation in NSCLC was determined as 58.0% for CDH1, 21.9% for p16INK4A, and 52.2% for FHIT. The methylation of p16INK4A was observed significantly in heavy smokers compared either with nonsmokers or with patients who had smoked for <20 pack-years (P = .0420); it also was more significant in squamous cell carcinomas than in adenocarcinomas (P = .0343). FHIT methylation also was correlated significantly with lymph node metastasis (P = .0361). Patients who had tumors with both methylation and reduced expression of CDH1 had a significantly poorer prognosis compared with patients who had tumors both without methylation and with positive expression of CDH1 (P = .0259 and P = .0369, respectively; multivariate Cox analysis). For p16INK4A methylation, 63.3% of tumors showed reduced expression; whereas, in p16INK4A-unmethylated tumors, 33.7% showed reduced expression (P = .0002). However, for CDH1 and FHIT, no significant correlation was found for either methylation or reduced expression. Although protein expression was not inactivated by methylation alone, p16 expression was inactivated strongly by methylation. In addition, the analysis of methylation and expression of CDH1 played a clinically important role in treatment strategies for patients with NSCLC.

Nakata S ，Sugio K ，Uramoto H ，Oyama T ，Hanagiri T ，Morita M ，Yasumoto K ... -  《CANCER》

Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas. An immunohistochemical and fluorescence in situ hybridization study.

Suzuki S ，Dobashi Y ，Sakurai H ，Nishikawa K ，Hanawa M ，Ooi A ... -  《CANCER》

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

Suzuki M ，Wada H ，Yoshino M ，Tian L ，Shigematsu H ，Suzuki H ，Alaa M ，Tamura H ，Fujiwara T ，Nagato K ，Motohashi S ，Moriya Y ，Hoshino H ，Yoshida S ，Shibuya K ，Hiroshima K ，Nakatani Y ，Yoshino I ... -  《-》

Synchronous alterations of Wnt and epidermal growth factor receptor signaling pathways through aberrant methylation and mutation in non small cell lung cancer.

Suzuki M ，Shigematsu H ，Nakajima T ，Kubo R ，Motohashi S ，Sekine Y ，Shibuya K ，Iizasa T ，Hiroshima K ，Nakatani Y ，Gazdar AF ，Fujisawa T ... -  《CLINICAL CANCER RESEARCH》