Synchronous Alterations of Wnt and Epidermal Growth Factor Receptor Signaling Pathways through Aberrant Methylation and Mutation in Non–Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 13; no. 20; pp. 6087 - 6092
• Main Authors: SUZUKI, Makoto, SHIGEMATSU, Hisayuki, GAZDAR, Adi F, FUJISAWA, Takehiko, NAKAJIMA, Takahiro, KUBO, Rieko, MOTOHASHI, Shinichiro, SEKINE, Yasuo, SHIBUYA, Kiyoshi, IIZASA, Toshihiko, HIROSHIMA, Kenzo, NAKATANI, Yukio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2007
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; DNA Methylation; DNA Mutational Analysis; EGFR; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Medical sciences; methylation; Middle Aged; Mutation; Pharmacology. Drug treatments; Pneumology; Prognosis; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Tumors of the respiratory system and mediastinum; Wnt; Wnt Proteins - genetics; Wnt Proteins - metabolism; Lung disease; Respiratory disease; Lung cancer; Malignant tumor; non-small cell lung carcinoma; Epidermal growth factor receptor; Signal transduction; Growth factor receptor; Signaling pathway; Bronchus disease; Genetics; Mutation; Methylation; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0591

Purpose: The Wnt and epidermal growth factor receptor (EGFR) signaling pathways play crucial roles in the pathogenesis of a variety of malignant tumors. Although the details of each cascade are understood, very little is known about their collective effects in non–small cell lung cancer (NSCLC). Experimental Design: A total of 238 NSCLC samples were examined for methylation of Wnt antagonists [secreted frizzled-related protein (sFRP)-1, sFRP-2, sFRP-5, Wnt inhibitory factor-1, and Dickkopf-3] and for EGFR and KRAS mutations. Protein expression levels of β-catenin were assayed in 91 of the 238 NSCLCs. Results: We found that ( a ) aberrant methylation of Wnt antagonists is common in NSCLCs; ( b ) methylation of sFRP-2 is more prevalent in females, nonsmokers, and adenocarcinoma cases; ( c ) Dickkopf-3 methylation is significantly associated with a poor prognosis in adenocarcinomas; ( d ) there is a positive correlation between activated EGFR mutation and nuclear accumulation of β-catenin; ( e ) KRAS mutation and aberrant methylation of Wnt antagonists are positively correlated; and ( f ) EGFR mutation is significantly associated with a good prognosis in tumors lacking methylated Wnt antagonist genes. Conclusions: These results contribute to a better understanding of the cross-talk between the Wnt and EGFR signaling pathways and help foster development of chemotherapeutic treatments in NSCLCs.