Hypermethylated PCDHGB7 as a Biomarker for Early Detection of Endometrial Cancer in Endometrial Brush Samples and Cervical Scrapings

Abstract

Endometrial cancer (EC) is one of the most common gynecologic cancers in developed countries. Presently, it is imperative to develop a reliable, noninvasive, or minimally invasive detection method for EC. We explored the possibility of using DNA methylation marker from endometrial brush samples (with a “Tao brush”) and cervical scrapes (with a “Pap brush”) for early detection of EC. We analyzed the methylation data of EC and normal endometrial tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. An optimized methylation-sensitive restriction enzyme combined with real-time fluorescent quantitative PCR (MSRE-qPCR) was used for methylation detection. Included in the training set were 143 endometrial tissues, 103 Tao, and 109 Pap brush samples. The validation set included 110 Tao and 112 Pap brush samples. PCDHGB7 was significantly hypermethylated in EC compared with normal endometrial tissues in the TCGA and GEO data sets (AUC >0.95), which was verified in clinical samples. In the Pap brush samples, the AUC was 0.86 with 80.65% sensitivity and 82.81% specificity, whereas the Tao brush samples exhibited higher specificity (95.31%). The combination of Tao and Pap brush samples significantly increased the sensitivity to 90.32%. In the validation set, the final model yielded a sensitivity of 98.61%, specificity of 60.53%, positive predictive value of 82.56%, and negative predictive value of 95.83%. These results demonstrate the potential application of the novel methylation marker, hypermethylated PCDHGB7, in cervical scrapings and endometrial brush, which provides a viable, noninvasive, or minimally invasive method for early endometrial cancer detection across different clinical features and histologies to supplement current hysteroscopy diagnosis.

Endometrial Cancer Detection by DNA Methylation Analysis in Cervical Papanicolaou Brush Samples

“…Similarly, previous reports documented 3-gene panel (BHLHE22-CDO1-CELF4/BHLHE22-CDO1-TBX5) or single gene-based (PCDHGB7) DNA methylation for EC detection using cervical scrapings, the ROC for these markers ranged from 0.80 to 0.94, or 0.86, respectively. 11 – 13 Also, Wang et al 26 reported a relevant study on methylation marker-based EC screening in endometrial cytological samples using Li Brush. Compared with endometrial sampling, cervical Pap brush sampling is a more acceptable screening tool for the general population.…”

“… 11 Similar studies furthermore demonstrated that cervical scrapings, instead of endometrium and blood, are a good source of DNA for molecular testing, and DNA methylated genes as biomarkers for EC detection from cervical scrapings is feasible and appealing. 11 – 13 However, relevant research is relatively uncommon.…”

New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions

“…In addition, gene methylation, especially in ADCYAP1 and HAND2 , can be identified prior to the diagnosis of EC [ 42 ]. Hypermethylated PCDHGB7 has been identified as a new cancer marker and is applicable in early screening for EC and CC [ 43 ]. Thus, abnormal DNA methylation could serve as a promising indicator for the detection of EC and CC.…”

Diagnosis of malignant body fluids via cancer-universal methylation in cell-free DNA

“…Previously, we have proposed the concept of universal cancer–only methylation (UCOM), a collection of cancer-specific epigenetic features shared among most cancer types ( 24 , 25 ). The clinical value of several markers has already been demonstrated in early diagnosis of specific cancer types, including lung cancer, cervical cancer, and endometrial cancer ( 24 , 26 , 27 ). However, the clinical utility of their pan-cancer characteristics remains to be demonstrated in a real-world study with diverse tumor types.…”