PAX1/SOX1 DNA methylation and cervical neoplasia detection: a Taiwanese Gynecologic Oncology Group (TGOG) study

Abstract

We aimed to determine whether PAX1/SOX1 methylation could be translated to clinical practice for cervical neoplasia detection when used alone and in combination with current cytology-based Pap screening. We conducted a multicenter case–control study in 11 medical centers in Taiwan from December 2009 to November 2010. Six hundred seventy-six patients were included in the analysis, including 330 in the training set and 346 in the testing set. Multiplex quantitative methylation-specific polymerase chain reaction (PCR) was performed with a TaqMan probe system using a LightCycler 480 Real-Time PCR System (Roche). The level of human papilloma virus (HPV) was analyzed using a Hybrid Capture 2 system (Digene). Receiver operating characteristic curves were generated to obtain the best cutoff values from the training data set. The sensitivities, specificities, and accuracies were validated in the testing set. The sensitivities for methylated (m) PAX1m and SOX1m and HPV testing for detecting CIN3+ lesions were 0.64, 0.71, and 0.89, and the specificities were 0.91, 0.77, and 0.68, respectively. Combined parallel testing of PAX1m/SOX1m tests with Pap smearing showed superior specificity (0.84/0.71 vs. 0.66, respectively) and similar sensitivity (0.93/0.96 vs. 0.97) to the combination of Pap smear results and HPV testing. Thus, combined parallel testing using Pap smears and PAX1 or SOX1 methylation tests may provide better performance than a combination of Pap smears with HPV testing in detection for cervical neoplasia.

Quantitative DNA methylation analysis of paired box gene 1 and LIM homeobox transcription factor 1 α genes in cervical cancer

“…These data revealed that the detection of PAX1 methylation has clinical diagnostic value in differentiating invasive CC, but may not be sufficient alone in screening for HSIL. A number of studies have indicated the potential value of PAX1 for the screening and detection of CC (49,51,52), in line with the findings of the present study, but the association between PAX1 and tumors requires further investigation. The present study used methylation-specific PCR to demonstrate that the PAX1 gene is abnormally methylated in cervical cancer specimens, with methylation rates as high as 87.5%, which is significantly different to those in normal cervical tissues and cervical precancerous lesions (49).…”

PAX1 and SOX1 methylation as an initial screening method for cervical cancer: a meta-analysis of individual studies in Asians

“…The sensitivity of HPV DNA testing is satisfactory, whereas the high prevalence of transient HPV infections had limited the specificity of this approach (10,11). Currently, there are several test methods for HPV DNA assay, such as PCR, hybrid capture II (HC2), strip test (for E6 detection) as well as other novel techniques (5,(12)(13)(14)(15)34,35), Among these evaluation tools, PCR and HC2 tests remain the most commonly used techniques (34,35). Notwithstanding, single HPV DNA testing using PCR or HC2 method seems to yield inconstant results for the detection of cervical precancerous lesions (CIN2 or worse).…”

“…Evidence from a recent study suggested that PAX1 methylation harbored a better diagnostic performance with a specificity of 0.88 when combined with sequential testing of HPV (14). In addition, the paneled assay of PAX1/SOX1 methylation has been previously described as well, which the sensitivity was greater than 0.70, and specificity greater than 0.90 (15).…”

“…Among these altered and methylated genes, the paired boxed gene 1 (PAX1) and sex determining region Y-box 1 (SOX1) were both highlighted (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Numerous studies have documented the promise of PAX1 or SOX1 DNA methylation in distinguishing patients with reactive atypia or CIN3+ (cervical intraepithelial neoplasia type III or worse) lesions from normal uterine cervixes (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). In order to make a comparison of the accuracy of DNA methylation and HPV DNA testing, we performed a comprehensive meta-analysis and evaluated the diagnostic performance of PAX1 and SOX1 methylation for cervical cancer screening.…”

Real-time colorimetric detection of DNA methylation of the <em>PAX1</em> gene in cervical scrapings for cervical cancer screening with thiol-labeled PCR primers and gold nanoparticles

“…15 Consequently, DNA methylation could be an effective biomarker for early diagnosis of cancers and prediction of prognosis in cancer patients. Previous studies showed the presence of aberrant DNA hypermethylation of classic tumor suppressor genes in cervical cancer; these genes include the paired box gene 1 (PAX1), 16 genes for sex-determining region Y-box 1, 17 epidermal growth factor receptor, cyclooxygenase-2, genes for protein tyrosine phosphatase receptor type R, 18 and zinc finger protein 582. 19 PAX1 shows the highest potential to be a methylation biomarker.…”