Triage of atypical glandular cell by SOX1 and POU4F3 methylation: A Taiwanese Gynecologic Oncology Group (TGOG) study

Introduction: Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC) are detected on Pap smear with unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures. Methods: We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed "AGC not otherwise specified" (AGC-NOS) were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR) was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3⁺ and endometrial complex hyperplasia. Results: In 55 patients with AGC, the sensitivity for methylated (^m) SOX1^m, PAX1^m, ZNF582^m, PTPRR^m, AJAP1^m, HS3ST2^m, and POU4F3^m for detecting CIN3⁺ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions. Conclusion: Methylated (^m) SOX1^mand POU4F3^mcould be new methylation biomarkers for detection of CIN3⁺ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1^m/ POU4F3^m, colposcopy, cervical conization or endometrial sampling should be considered.