A three-gene signature and clinical outcome in esophageal squamous cell carcinoma

Ling-Ling Sun, Jian-Yi Wu, Zhi-Yong Wu, Jin-Hui Shen, Xiu-E Xu, Bo Chen, Shao-Hong Wang, En-Min Li, Li-Yan Xu, Ling-Ling Sun, Jian-Yi Wu, Zhi-Yong Wu, Jin-Hui Shen, Xiu-E Xu, Bo Chen, Shao-Hong Wang, En-Min Li, Li-Yan Xu

Abstract

It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications. GASC1, member of the histone demethylases affecting heterochromatin formation and transcriptional repression, has been found to be dysregulation in many types of cancers including breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia. In this study, we examined the expression of GASC1 and certain GASC1-targeted genes (KLF4, MYC, SOX2, PPARG, MDM2, and NANOG) and identified a three-gene prognostic signature (PPARG, MDM2, and NANOG), using risk scores based on immunohistochemical analyses of 149 tumor specimens from patients with esophageal squamous cell carcinoma (ESCC). The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients. We validated the predictive value of the three-gene signature in a second independent cohort of 101 patients with ESCC in order to determine whether it had predictive value. The results were similar to those in 149 patients. According to multivariate Cox proportional hazards analyses, the predictive model of a three-gene signature was an independent predictor for OS (p = 0.005 in cohort 1, p = 0.025 in cohort 2). In addition, ROC analysis indicated that the predictive ability of the three-gene model was more robust than that of a single biomarker. Therefore, our three-gene signature is closely associated with OS among patients with ESCC and may serve as a predictor for the poor prognosis of ESCC patients.

Keywords: esophageal squamous cell carcinoma; gene prognostic signature; histone demethylase; histopathology.

© 2014 UICC.

Figures

Figure 1
Figure 1
Representative positive/negative expression of KLF4, MYC, SOX2, GASC1, PPARG, MDM2, and NANOG by immunochemistry study in tissue microarrays. The bar indicates 50 μm.
Figure 2
Figure 2
Kaplan-Meier estimates of survival of patients with ESCC according to the three-gene signatures as measured by immunohistochemistry. In cohort 1, overall survival is shown for the 149 patients with ESCC (a), for the 127 patients with invasive depth 3 (T3) or invasive depth 4 (T4) disease (b), and for the 99 patients with differentiation grade 2 (G2) disease (c). Overall survival is also shown for the independent cohort 2 of 101 patients (d), for the 88 patients in cohort 2 who had T3 or T4 disease (e), and for the 77 patients in cohort 2 who had G2 disease (f).
Figure 3
Figure 3
The predictive ability of the three-gene signature compared with single markers by receiver operating characteristic (ROC) curves (a in cohort 1 and b in cohort 2) and areas under the curve (AUC) with 95% CI (c in cohort 1 and d in cohort 2). The results show that the predictive ability of the three-gene model was more robust than that of a single biomarker.

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