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Expression of DNMT3B Variants and Its Association with Promoter Methylation of p16 and RASSF1A in Primary Non–Small Cell Lung Cancer

¹ Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, ² Department of Thoracic and Cardiovascular Surgery, and ³ Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ⁴ Department of Oncology, Beijing Cancer Hospital, Beijing University School of Oncology, Beijing, China

Requests for reprints: Li Mao, Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-796-8655; E-mail: lmao{at}mdanderson.org.

Despite the role of DNMT3B in de novo DNA methylation, a correlation between DNMT3B expression and promoter DNA methylation has not being established in tumors. We recently reported DNMT3B, a subfamily of DNMT3B, with seven variants, as the predominant expression forms in non–small cell lung cancer (NSCLC). We hypothesized that expression of the DNMT3B variants plays a role in promoter methylation formation during lung tumorigenesis. Expression of seven DNMT3B variants was measured in 119 NSCLCs and the corresponding normal lungs using reverse transcription-PCR. The expression patterns of DNMT3B variants were analyzed with the status of p16 and RASSF1A promoter methylation in the tumors as well as in patients' clinical variables, including outcomes. Expression of DNMT3B variants was detected in 94 of 119 (80%) tumors but in only 22 (18%) of the corresponding normal lungs (P < 0.0001). DNMT3B1, DNMT3B2, and DNMT3B4 were the most frequently detected transcripts in the tumors (62%, 76%, and 46%, respectively). The expression of DNMT3B variants was associated with p16 and RASSF1A promoter methylation in the tumors, but the strongest association was between DNMT3B4 and RASSF1A. Forty-two of 46 (91%) tumors with RASSF1A promoter methylation expressed DNMT3B4 compared with only 13 of 73 (18%) tumors without the promoter methylation (P < 0.0001). Strong associations were also observed between expression of the variants in the tumors and in patients' clinical outcomes. Expression of DNMT3B variants is common in NSCLC and may play an important role in the development of promoter methylation. (Cancer Res 2006; 66(17): 8361-6)

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