SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis

Abstract

Background: The increased risk and poor survival outcome of cervical adenocarcinoma (CAC) demand for effective early diagnostic biomarkers that can predict the disease progression and outcome. The purpose of this study was to investigate the value of methylation status of SOX1 and PAX1 in the detection and prognosis of CAC.

Methods: We performed a quantitative methylation-specific polymerase chain reaction in 205 cervical paraffin-embedded specimens (175 CACs, 30 noncancer cervical tissues). Overall and progression-free survival (OS and PFS, respectively) rates were calculated and compared using the Kaplan-Meier method. The prognostic value of SOX1^m and PAX1^m on CAC patients was assessed by the Cox regression model. A mathematical formula combining SOX1^m , PAX1^m , and age was constructed for survival prediction.

Results: The methylation status of SOX1 and PAX1 was higher in CAC tissues than in noncancer cervical tissues. In addition, SOX1^m -positive CAC patients showed a higher 5-year OS rate than SOX1^m -negative patients. In CAC patients with smaller tumor size (<4 cm), the PAX1^m -positive group showed a higher 5-year PFS rate than the PAX1^m -negative group. In the algorithm combining SOX1^m , PAX1^m , and age, the low-risk group showed a better 5-year OS and PFS rate than the high-risk group.

Conclusion: SOX1 and PAX1 methylation levels are higher in CAC than in normal cervical tissues and are potential biomarkers for monitoring CAC prognosis.

Figure 1

SOX1 and PAX1 methylation levels in cervical adenocarcinoma. (a) Methylation-Index (M-Index) of SOX1 and PAX1 methylation between the noncancer group (30 noncancer tissues) and cervical cancer group (175 adenocarcinoma), p < 0.01; (b) the area under the ROC curve for the SOX1 and PAX1 methylation assay was calculated for exploring cervical cancer. The sensitivity and specificity of SOX1 methylation were 87.22% and 56.67%, respectively, with a cut-off point of ∆Cp = 11. The AUC was 88.42%. And the sensitivity and specificity of PAX1 methylation were 40.30% and 100%, separately, with a cut-off point of ∆Cp = 9. The AUC was 70.80%.

Figure 2

Association of SOX1 and PAX1 methylation status with CAC patients' survival. (a) SOX1^m-positive patients have a longer OS rate than SOX1^m-negative patients (93.35% vs. 68.29%, p = 0.048); (b) in CAC patients with smaller tumor size (<4 cm), PAX1^m-positive group had a higher 5-year PFS rate than the PAX1^m-negative group (100% vs. 82.4%, p = 0.044).

Figure 3

Algorithm combining clinicopathologic factor and genetic test results. The algorithm divided patients into high-risk and low-risk groups. The low-risk group showed a better 5-year overall survival (OS) rate (95.89% vs. 81.47%, p = 0.019) (a) and better 5-year progression-free survival (PFS) rate (90.58% vs. 72.50%, p = 0.006) than the high-risk group (b).