Methylation of PAX1 gene promoter in the prediction of concurrent chemo-radiotherapy efficacy in cervical cancer

Abstract

Objectives: Cervical cancer is the fourth leading cause of cancer death among women worldwide. In currently, aberrant methylation of PAX1 is found in variety of solid tumors, including cervical cancer. In addition, the role of PAX1 gene methylation in cervical cancer and precancerous lesions screening has been confirmed in previous study. Here, we evaluated the predictive value of PAX1 methylation in concurrent chemo-radiotherapy (CCRT) outcomes in cervical cancer. Methods: This study enrolled 82 cervical cancer patients from August 2018 to August 2020. We compared the clinical results between different PAX1 methylation status. Hyper-methylation patients were subjects to MRI and quantitative methylation-specific PCR (QMSP) for PAX1 before, in the middle, immediately after, 1 month and 3 months after CCRT. The changes in PAX1 methylation during CCRT were analyzed. Results: The lower PAX1 methylation status were related to a poor tumor response. Based on the MRI findings three months post-treatment, the hypermethylated patients were classified into the complete response (CR; n=50) and partial remission (PR; n=18) groups. The average PAX1 △Cp value of CR and PR groups before radiotherapy was 5.08±1.98 and 4.32±2.00 respectively, and after concurrent chemo-radiotherapy was significantly increased to 17.35±4.96 and 16.99±6.17, respectively (P<0.05). Furthermore, the PAX1 △Cp value between CR and PR groups were significantly different at mid-treatment and performed well in predicting short-term efficacy (AUC 0.84) in this period, and its sensitivity and specificity for predicting PR were 0.72 and 0.88, respectively. Conclusion: The PAX1 methylation level may predict the sensitivity and efficacy of CCRT in cervical cancer.

Promising predictive molecular biomarkers for cervical cancer (Review)

“…However, methylation level changes in PAX1, that were evaluated using relative quantification (ratio of PAX1/COL2A methylation), were associated with an improved response in patients treated with RT. The reduction in methylation levels of PAX1 in stage IIB/IIIB tumors during the RT phase was significantly correlated with smaller tumor size, which was observed in patients with CR ( 106 ). An analysis of cutoff values (delta CP ≤9) showed that differences in PAX1 methylation, observed during the RT phase, could predict a failed response to treatment with high sensitivity (72%) and specificity (88%).…”

Association and Effectiveness of PAX1 Methylation and HPV Viral Load for the Detection of Cervical High-Grade Squamous Intraepithelial Lesion

“…In addition, PAX1 m can be used for screening women with atypical squamous cells of undetermined significance (ASCUS) and has also shown better diagnostic performance than HPV-DNA in predicting high-grade CIN (CIN2/3) [ 25 ]. PAX1 m has also been reported to predict the efficacy of concurrent chemo-radiotherapy in cervical cancer [ 26 ]. In this study, PAX1 m increased significantly in CIN3 and strikingly the highest in SCC, but could not distinguish CIN2 from CIN1.…”

An overview of PAX1: Expression, function and regulation in development and diseases

“…In the last decade, a growing body of evidence has implied an emerging tumor suppressing role of PAX1 in various human cancers, including cervical cancer ( Huang et al, 2010 ; Kan et al, 2014 ; Lai et al, 2014 ; Liu H. et al, 2020 ; Li et al, 2021 ), ovarian cancer ( Hassan et al, 2017 ), colorectal carcinoma ( Huang et al, 2017 ), parathyroid tumor ( Singh et al, 2022 ), as well as oral squamous cell carcinoma ( Huang et al, 2014 ; Cheng et al, 2018 ; Sun et al, 2020 ), and so on. Higher DNA methylation levels of PAX1 were observed in most kinds of cancer cells ( Lai et al, 2008 ; Huang et al, 2010 ; Cheng et al, 2016 ; Huang et al, 2016 ; Huang et al, 2017 ; Su et al, 2019 ; Tang et al, 2019 ; Zhao et al, 2020 ; Singh et al, 2022 ), significantly strengthened the observation that PAX1 often acts as a tumor suppressor.…”

“…Epigenetic changes are recognized to occur in the early stage of tumor progress and in advanced of genetic alterations, thereby affording a reason for developing biomarkers for early identification and prevention of cancer ( Reis et al, 2016 ). Therefore, PAX1 methylation level not only can provide biomarkers for early detection and diagnosis in cancer patients, but also could predict and monitor early therapeutic response ( Pan et al, 2018 ; Li et al, 2021 ).…”