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<p>Abstract</p> <p>Background</p> <p>It is well known that genetic alternation of epidermal growth factor receptor (<it>EGFR</it>) plays critical roles in tumorgenesis of lung cancer and can predict outcome of non-small-cell lung cancer treatment, especially the EGFR tyrosine-kinase inhibitors (EGFR-TKIs) therapy. However, it is unclear whether epigenetic changes such as DNA methylation involve in the response to the EGFR-TKI therapy.</p> <p>Methods</p> <p>Tumor samples from 155 patients with stages IIIB to IV NSCLC who received EGFR-TKI therapy were analyzed for DNA methylation status of Wnt antagonist genes, including <it>SFRP1</it>, <it>SFRP2</it>, <it>SFRP5</it>, <it>DKK3</it>, <it>WIF1</it>, and <it>APC</it>, using methylation specific PCR (MSP) method. EGFR mutations detections were performed in the same tissues samples using Denaturing High Performance Liquid Chromatography (DHPLC).</p> <p>Results</p> <p>We found that Wnt antagonists tend to methylate simultaneously. Methylation of sFRP1 and sFRP5 are reversely correlated with EGFR mutation (P = 0.005, P = 0.011). However, no correlations of methylations of other Wnt antagonist genes with EGFR mutation were found. The patients with methylated <it>SFRP5</it> have a significant shorter progression free survival than those with unmethylated <it>SFRP5</it> in response to EGFR-TKI treatment (P = 0.002), which is independent of <it>EGFR</it> genotype.</p> <p>Conclusions</p> <p>Patients with unmethylated <it>SFRP5</it> are more likely to benefit from EGFR-TKI therapy.</p>