Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer
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Shunlin Liu1,*, Xiaoying Chen2,*, Ruhua Chen3,*, Jinzhi Wang4,*, Guoliang Zhu5, Jianzhong Jiang6, Hongwei Wang7, Shiwei Duan2, Jianan Huang1
1Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
2Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
3Department of Respiratory Medicine, Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, China
4Department of Cell Biology, School of Medicine, Soochow University, Suzhou, Jiangsu 215007, China
5Department of Pathology, Huzhou First People's Hospital, Huzhou, Zhejiang 313000, China
6Department of Geriatrics, Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, China
7Realgen Biotechnology Co., Ltd. Zhangjiang High Technology Park, Shanghai 201203, China
Jianan Huang, email: firstname.lastname@example.org
Shiwei Duan, email: email@example.com
Keywords: non-small cell lung cancer, quantitative methylation-specific PCR, DNA methylation, diagnosis, Wnt pathway
Received: November 22, 2016 Accepted: March 21, 2017 Published: March 31, 2017
Wnt signal pathway genes are known to be involved with cancer development. Here we tested the hypothesis whether DNA methylation of genes part of the Wnt signaling pathway could help the diagnosis of non-small cell lung cancer (NSCLC). The methylation levels of SFRP1, SFRP2, WIF1 and PRKCB in 111 NSCLC patients were evaluated by quantitative methylation-specific PCR (qMSP). Promoter methylation levels of four candidate genes were significantly higher in tumor tissues compared with the adjacent tissues. SFRP1, SFRP2 and PRKCB genes were all shown to be good predictors of NSCLC risk (SFRP1: AUC = 0.711; SFRP2: AUC = 0.631; PRKCB: AUC = 0.650). The combined analysis showed that the methylation status of the four genes had a sensitivity of 70.3% and a specificity of 73.9% in the prediction of NSCLC risk for study cohort. A higher diagnostic value with an AUC of 0.945 (95% CI: 0.923–0.967, sensitivity: 90.6%, specificity: 93.0%) was found in TCGA cohort. In addition, SFRP1 and SFRP2 hypermethylation events were specific to male patients. Further TCGA data mining analysis suggested that SFRP1_cg15839448, SFRP2_cg05774801, and WIF1_cg21383810 were inversely associated with the host gene expression. Moreover, GEO database analysis showed that 5'-Aza-deoxycytidine was able to upregulate gene expression in several lung cancer cell lines. Subsequent dual-luciferase reporter assay showed a crucial regulatory function of PRKCB promoter. In summary, our study showed that a panel of Wnt signal pathway genes (SFRP1, SFRP2, WIF1 and PRKCB) had the potential as methylation biomarkers in the diagnosis of NSCLC.
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