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Expression of D DNMT 3 B Variants and Its Association with Promoter Methylation of p 16 and RASSF 1 A in Primary Non – Small Cell Lung Cancer

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 DDNMT3B , 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 DDNMT3B variants plays a role in promoter methylation formation during lung tumorigenesis. Expression of seven DDNMT3B variants was measured in 119 NSCLCs and the corresponding normal lungs using reverse transcription-PCR. The expression patterns of DDNMT3B 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 DDNMT3B variants was detected in 94 of 119 (80%) tumors but in only 22 (18%) of the corresponding normal lungs (P < 0.0001). DDNMT3B1, DDNMT3B2 , and DDNMT3B4 were the most frequently detected transcripts in the tumors (62%, 76%, and 46%, respectively). The expression of DDNMT3B variants was associated with p16 and RASSF1A promoter methylation in the tumors, but the strongest association was between DDNMT3B4 and RASSF1A . Forty-two of 46 (91%) tumors with RASSF1A promoter methylation expressed DDNMT3B4 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 DDNMT3B variants is common in NSCLC and may play an important role in the development of promoter methylation. (Cancer Res 2006; 66(17): 8361-6)