DAB2 interactive protein (DAB2IP) methylation in serum DNA of non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

Abstract

7593 Background: DAB2IP loss promotes primary tumor growth by activating Ras and drives metastasis through NFkB, serving as a signaling scaffold to coordinately regulate these pathways. DAB2IP is frequently methylated in lung cancer, and methylation in the m2a region is a key regulatory factor for DAB2IP expression in prostate cancer. We examined DAB2IP methylation in cell lines and in serum from erlotinib-treated NSCLC p with EGFR mutations. Methods: In human lung, breast and colorectal cancer cell lines, we analyzed DAB2IP promoter methylation in regions m2a and m2b by methylation-specific PCR (MSP) and bisulfite genomic sequencing. In circulating serum DNA from 152 erlotinib-treated NSCLC p with EGFR mutations, we analyzed methylation in the m2a and m2b promoter regions of DAB2IP by MSP. Methylation status was correlated with clinical outcome. Results: Methylation was detected in the m2a region of 42 (27.63%) p, and in the m2b region in 51 (33.55%) p. There were no major differences in clinical characteristics (age, gender, smoking history, EGFR mutation type, metastatic sites) between p with methylation in the m2a region and p with methylation in the m2b region. Overall progression-free survival (PFS) was 15 months (m), and median survival (MS) 28 m for all 152 p. For the 41 p with bone metastases (mets), PFS was 14 m for 30 p without methylation in the m2a region vs 8 m for 11 p with methylation in the m2a region (P=0.01), and MS was 23 m vs 10 m, respectively (P=0.19). For the 57 p with distant mets but no lung mets, PFS was 18 m for 36 p without methylation in the m2a region vs 10 m for 21 p with methylation in the m2a region (P=0.01), and MS was 24 m vs 16 m, respectively (P=0.03). No differences in either PFS or MS were observed according to the methylation status of the m2b region. Conclusions: Methylation in the m2a region of DAB2IP in serum DNA correlates with PFS and MS to erlotinib in NSCLC p with EGFR mutations with non-lung mets. Surveillance of DAB2IP methylation status in circulating DNA could be a useful tool to predict outcome to erlotinib in EGFR-mutated NSCLC p with non-lung mets.