Age-Related CDKN2A (p16) Promoter Methylation and Outcome in Surgically Treated Stage I-II Non-Small Cell Lung Cancer Patients
DP Bradly, L Buckingham, J Coon, M Liptay, P Bonomi, P Gattuso. Rush University Medical Center, Chicago, IL
Background: Non-small cell lung cancer (NSCLC) is a disease that infrequently occurs in younger individuals (< 40 years of age). Currently, no biological indicators accurately differentiate NSCLC in these patients from those that occur in older individuals. To explore epigenetic influences, promoter methylation (silencing) at multiple CpG dinucleotides of selected tumor suppressor genes was analyzed in stage I and II NSCLC patients.
Design: Methylation was quantified at specific CpG sites in p16, MGMT, DAPK, RASSF1, CDH1, LET7-3-a, NORE1(RASSF5), and PTEN promoters in assessable tumor tissue from 196 surgically treated NSCLC patients by pyrosequencing. Molecular and clinical characteristics with time to recurrence (TTR) and overall survival (OS) were evaluated.
Results: Methylation levels of specific promoter sites in DAPK and CDH1 were significantly higher in patients with age at diagnosis over 50 years (n=167) than in those patients with diagnosis at 50 years or younger (n=29). Methylation levels at all 7 potentially hypermethylated cytosine positions tested in the p16 promoter (-64 to -40; A of ATG = +1) were significantly higher in the >50 group than in the ≤50 group (p=0.001 – 0.012). The results were more significant using a cutoff of 40 years or younger (p<0.001). In Kaplan-Meier analysis, patients with age at diagnosis ≤40 years had shorter median TTR than those over 40 years (18.3 mos vs 114 mos, Log rank p=0.018). When p16 was hypermethylated at cytosine position -49, patients with diagnosis ≤ 50 years had significantly shorter TTR (9.9 mos vs 78.8 mos; p=0.098) and significantly shortened OS (14.9 mos vs 125 mos; p=0.008). No such effect was seen in patients >50.
Conclusions: Although P16 methylation had the highest frequency in patients > 50 years, it was associated with a worse outcome in patients ≤ 50 years who had hypermethylation at cytosine position -49. Overall, these data support an influence of hypermethylation in the p16 promoter and outcome in young patients (≤50 years) after surgical resection for stage I and II NSCLC.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 237, Wednesday Morning