DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer

Jian Zhu,Hua Bai,Jun Zhao,Lu Yang,Shuhang Wang,Minglei Zhuo,Meina Wu,Yuyan Wang,Zhijie Wang,Jie Wang,Tongtong An,Lai Wei,Jianchun Duan

doi:10.1186/1756-9966-31-80

Abstract

BackgroundIt is well known that genetic alternation of epidermal growth factor receptor (EGFR) 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.MethodsTumor 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 SFRP1, SFRP2, SFRP5, DKK3, WIF1, and APC, using methylation specific PCR (MSP) method. EGFR mutations detections were performed in the same tissues samples using Denaturing High Performance Liquid Chromatography (DHPLC).ResultsWe 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 SFRP5 have a significant shorter progression free survival than those with unmethylated SFRP5 in response to EGFR-TKI treatment (P = 0.002), which is independent of EGFR genotype.ConclusionsPatients with unmethylated SFRP5 are more likely to benefit from EGFR-TKI therapy.

Highlights

It is well known that genetic alternation of epidermal growth factor receptor (EGFR) 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
In 2004, three research groups reported that mutations in the tyrosine kinase domain of EGFR can predict the responses to TKIs in NSCLC patients [12,13,14], which enables the identification of patient populations that are more likely to benefit from TKI therapies and serves as the first step toward personalizing lung cancer therapy
The methylation status of Wnt antagonist genes including SFRP1, SFRP2, SFRP5, WIF1, DKK3, APC, and CDH1, defined as their epigenotype, was detected by Methylation Specific PCR Assays

Summary

Introduction

It is well known that genetic alternation of epidermal growth factor receptor (EGFR) 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. According to the theory of “EGFR addition”, which refers to the dependency of cancer cells on EGFR mutation to maintain their malignant phenotypes [15], lung cancer patients harboring mutations in the tyrosine kinase domain of their EGFR genes should survive much longer, in response to the EGFR-TKI therapy, than the actual result. This suggested that EGFR mutation cannot explain all clinical outcomes of TKI therapy. Factors in addition to EGFR genotype may contribute to the response to EGFR-TKI therapy

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Conclusion