Validation of a cervical CDO1/CELF4 methylation test for endometrial cancer: a prospective paired-sample comparison with intrauterine specimen

BackgroundThe increasing global incidence of endometrial cancer (EC) underscores the urgent need for effective early detection. Noninvasive detection approaches, such as transvaginal ultrasonography (TVS), frequently exhibit low specificity, leading to a high rate of unnecessary invasive procedures. DNA methylation analysis has emerged as a promising noninvasive alternative. This study aimed to validate CDO1/CELF4 gene methylation analysis for detecting endometrial intraepithelial neoplasia (EIN) and EC and, critically, to compare its diagnostic efficacy using noninvasive cervical brushing cells (CBCs) vs. invasive diagnostic curettage (D&C) samples.MethodsA prospective paired-samples study was conducted at Gansu Provincial Maternity and Child Care Hospital (July 2023�CJune 2024), including 226 eligible women. CBC and D&C samples were collected sequentially from each participant and tested for CDO1/CELF4 methylation, with diagnostic performance and consistency compared between sample types.ResultsAmong 226 participants, 31 were diagnosed with EIN or EC. Compared with conventional markers (cytology, endometrial thickness, and CA125 levels), individual CDO1, CELF4, and CISENDO (CDO1/CELF4) methylation tests from both CBC and D&C samples demonstrated superior diagnostic capabilities. Specifically, the ��Ct values of CDO1 and CELF4 were significantly lower in patients with EIN or EC than in those with benign lesions (P < 0.0001 for all comparisons). A strong positive correlation was observed between CBC and D&C samples for individual methylated CDO1 tests (R = 0.86) and CELF4 tests (R = 0.78), suggesting a high agreement. ROC analysis confirmed no statistically significant difference in diagnostic accuracy between CBC and D&C samples for the CISENDO test (P = 0.244). The CISENDO test achieved an AUC of 0.929, with 93.5% sensitivity and 92.3% specificity using D&C samples, and an AUC of 0.916 with CBC samples when using manufacturer-recommended cutoff.ConclusionCDO1/CELF4 methylation analysis in cervical brushing samples is a highly accurate and reliable method for detecting EC and precursors, and no statistically significant difference in efficacy was observed compared to that of endometrial tissue tests. Its noninvasive nature can overcome significant diagnostic barriers, holding considerable promise as an effective triage tool for high-risk or symptomatic women, potentially revolutionizing early detection of EC and improving patient outcomes.