Therefore, in addition to genetic alterations, changes in epigenetic features such as CpG DNA methylation status of specific gene loci also mark the progress of cancers. Our current study showed that methylation of Wnt antagonist SFRP5 gene before treatment, independent of the genotype of EGFR gene, correlated with decreased progression free survival rate in NSCLC patients in response to the EGFR-TKI therapy. To our knowledge, this is the first report indicating that DNA methylation
Sotrastaurin chemical structure at specific gene loci in patient may predict drug response to the EGFT-TKI therapy. Both genetic and epigenetic risk factors for NSCLC have been studied extensively. Suzuki et al  has reported that methylation of the Wnt antagonist DKK3 correlated with low survival rate in NSCLC patients, despite of Selleck Poziotinib the different therapies patients received. However, in our study, we did not find significant difference in the EGFR-TKI responses between patient groups with or without methylated DKK3 (Additional file 1: Figure S2 and S3). In contrast, our results
suggested epigenotype of SFRP5 provide better prognostic estimation for the EGFR-TKI response, comparing to other Wnt antagonists. SFRP5 is a member of the SFRP protein family containing a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. It acts as soluble antagonist of Wnt signaling and is highly expressed in the retinal pigment epithelium, and moderately expressed in the pancreas (“”Entrez Gene: SFRP5 secreted frizzled-related protein 5″”). Previous studies has identified
association of SFRP5 promoter hypermethylation with Acute myeloid leukemia , ovarian cancer , gastric cancer , oral squamous cell carcinoma , pancreatic cancer  and breast cancer . We found that hypermethylation of SFRP5 predicted worse outcomes of the EGFR-TKI therapy. Therefore, SFRP5 DNA methylation status may serve as Bortezomib molecular weight a prognostic molecular marker for appropriately predicting whether NSCLC patients would benefit from the EGFR-TKI therapy. Especially, it is interesting that in the subgroup with adenocarcinoma and EGFR mutation, patients with sFRP5 methylation have a significantly shorter PFS than those without sFRP5 methylation, While in nonsmokers without EGFR mutation, patients without sFRP1 methylation have a longer PFS compared with patients with its methylation(9.7 ms vs 2.0 ms, p = 0.05). Based on these results, we can make a hypothesis that activation of Wnt signaling by antagonist methylation could confer tumors the characters of stem cell, which consequently causes tumors resistant to EGFR TKIs therapy by generating acquired resistance, such as MET amplification or changes of PTEN tumor suppressor activity and so on. Further study is needed to validate this hypothesis. Conclusions In conclusion, our study revealed that sFRP5 may be an independent factor affecting PFS during long time maintenance of TKIs therapy.