Gun Oh Chong

Microbial metabolites control self-renewal and precancerous progression of human cervical stem cells

Cervical cancer is the fourth most common female cancer, with the uterine ectocervix being the most commonly affected site. However, cervical stem cells, their differentiation, and their regulation remain poorly understood. Here, we report the isolation of a population enriched for human cervical stem cells and their regulatory mechanisms. Using single-cell RNA sequencing, we characterize the cellular heterogeneity of the human ectocervix and identify cluster-specific cell surface markers. By establishing normal and precancerous cervical organoids and an intralingual transplantation system, we show that ITGB4 and CD24 enable enrichment of human and murine ectocervical stem cells. We discover that Lactobacilli-derived lactic acid regulates cervical stem cells' self-renewal and early tumorigenesis through the PI3K-AKT pathway and YAP1. Finally, we show that D-lactic acid suppresses growth of normal and precancerous organoids, while L-lactic acid does not. Our findings reveal roles of human cervical stem cells and microbial metabolites in cervical health and diseases.

Discrepancy between Cytology and Histology in Cervical Cancer Screening: a Multicenter Retrospective Study (KGOG 1040)

Cervical cancer is the fourth common cancer in women worldwide. The Papanicolau test is the primary screening procedure to detect abnormal cervical cells. Colposcopy is the main procedure for discriminating high-grade cervical lesions. The study aimed at clarifying the discrepancy between cervical cytology and colposcopic biopsy histology as well as confounding factors. Eligible patients visited thirteen tertiary hospitals for colposcopic biopsy following cervical cytology and human papillomavirus (HPV) genotypes between January and December 2018. Baseline characteristics including age, body mass index (BMI), and parity were collected. In our study, 3,798 eligible patients were included. Mean age of patients was 42.7 (19-88) years and mean BMI was 22.5 (16.9-34.1) kg/m². The referred cervical cytologic findings consisted of 495 normal, 1,390 atypical squamous cells of undetermined significance, 380 atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, 792 low-grade squamous intraepithelial lesion, 593 high-grade squamous intraepithelial lesion, 79 atypical glandular cells, 46 squamous cell carcinoma, and 23 adenocarcinoma. HPV-positive findings were found in 3,008 (79.2%) patients and were not detected in 914 (24.1%) cases. The risk of unexpected low-grade lesions from histology was higher in patients > 45 years (odds ratio [OR], 2.137; 95% confidence intervals [CIs], 1.475-3.096). In contrast, the risk of unexpected high-grade lesions from colposcopic biopsy was lower in patients ≥ 45 years (OR, 0.530; 95% CI, 0.367-0.747) and HPV 16/18 infection was higher than other HPV (OR, 1.848; 95% CI, 1.385-2.469). Age and HPV genotypes were responsible for the discrepancies between cytology and histology. Precautions should be taken for women over the age of 45 in triage for colposcopy in order to avoid unnecessary testing.

Comparative performance of various human papillomavirus assays available in Korea for detecting cervical intraepithelial neoplasia

AbstractAimThe aim of this study was to evaluate the clinical performance for detecting cervical intraepithelial neoplasia (CIN) 2 or higher lesions among available human papillomavirus infection (HPV) genotyping tests in Korea.MethodsEligible patients visited 13 tertiary hospitals for colposcopic biopsy following cervical cytology and HPV genotyping test between January and December 2018. Baseline characteristics including age, body mass index (BMI), and parity were collected from 3798 patients. The performance of the Roche Cobas HPV 4800 was evaluated against other domestic HPV assays to detect CIN2 or higher.ResultsA total of seven types of HPV genotyping tests were analyzed in the research institutes. A total of 1358 patients (35.8%) tested Anyplex II HPV 28 and 701 patients (18.5%) tested Cobas 4800 HPV. The overall sensitivity in the detection of CIN2 or higher was 41.5% (38.9–44.1) in patients positive for HPV 16/18.The Cobas test for HPV 16/18 was concordant with other assays evaluated for detection of CIN2 or higher and showed sensitivity of 46.6%, which was not significantly different from other assays. Although Anyplex II HPV28 (Seegene) showed slightly decreased sensitivity for detecting CIN2 or higher lesion with HPV 16/18 positive (39.8%, p < 0.05) compared to Cobas 4800, in aspect of high‐risk HPV positive, Anyplex II HPV28 showed increased sensitivity (96.9%, p < 0.05).ConclusionThe performance of the HPV genotype test that were commonly used in Korea was concordant with Cobas HPV test. Further studies are needed to evaluate the safety, efficiency, and cost‐effectiveness of the various commercially available domestic HPV assays.

Transcriptomic Immune Profiles Can Represent the Tumor Immune Microenvironment Related to the Tumor Budding Histology in Uterine Cervical Cancer

Tumor budding (TB) histology has become a critical biomarker for several solid cancers. Despite the accumulating evidence for the association of TB histology with poor prognosis, the biological characteristics of TB are little known about in the context related to the tumor immune microenvironment (TIME) in uterine cervical cancer (CC). Therefore, this study aimed to identify the transcriptomic immune profiles related to TB status and further provide robust medical evidence for clinical application. In our study, total RNA was extracted and sequenced from 21 CC tissue specimens. As such, 1494 differentially expressed genes (DEGs) between the high- and low-TB groups were identified by DESeq2. After intersecting the list of DEGs and public immune genes, we selected 106 immune-related DEGs. Then, hub genes were obtained using Least Absolute Shrinkage and Selection Operator regression. Finally, the correlation between the hub genes and immune cell types was analyzed and four candidate genes were identified (one upregulated (FCGR3B) and three downregulated (ROBO2, OPRL1, and NR4A2) genes). These gene expression levels were highly accurate in predicting TB status (area under the curve >80%). Interestingly, FCGR3B is a hub gene of several innate immune pathways; its expression significantly differed in the overall survival analysis (p = 0.0016). In conclusion, FCGR3B, ROBO2, OPRL1, and NR4A2 expression can strongly interfere with TB growth and replace TB to stratify CC patients.