Dataset Information

Over Expressed TKTL1, CIP-2A, and B-MYB Proteins in Uterine Cervix Epithelium Scrapings as Potential Risk Predictive Biomarkers in HR-HPV-Infected LSIL/ASCUS Patients.

ABSTRACT: High oncogenic risk human papillomaviruses (HR-HPVs) promote cervical carcinoma development, the fourth most common feminine cancer. A slow oncodevelopmental phase-defined histopathologically as Cervical Intraepithelial Neoplasia (CIN) grades 1-3, or cytologically as Low- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL)-precedes the malignancy. Cervical carcinoma screenings through HR-HPV genotyping and Pap smears are regularly performed in Western countries. Faulty cytology screening or genotyping or patients' non-compliance with follow-ups can let slip an oncoprogression diagnosis. Novel biomarker tests flanking HR-HPV genotyping and cytology could objectively predict the risk of disease progression thus helping triage LSIL/ASCUS patients. Here, anonymized leftovers of fresh cervical epithelium scrapings from twice (LSIL/ASCUS and HR-HPV DNA)-positive and twice (Pap smear- and HR-HPV DNA)-negative (control) patients in a proteome-preserving solution served to assess the biomarker worth of three cervical carcinoma-related proteins, i.e., B-MYB (or MYBL2), Cancerous Inhibitor of PP2A (CIP-2a), and transketolase-like1 (TKTL1). Leftovers anonymity was strictly kept and storage at -80°C, protein extraction, immunoblotting, and band densitometry were blindly performed. Only after tests completion, the anonymous yet code-corresponding HR-HPV-genotyping and cytology data allowed to assign each sample to the twice-positive or twice-negative group. Descriptive statistics showed that the three proteins levels significantly increased in the twice-positive vs. twice-negative scrapings. Diagnostic ROC curve analysis identified each protein's Optimal Decision Threshold (OTD) showing that TKTL1 and CIP-2a are stronger risk predictive biomarkers (Sensitivity, 0.91-0.93; Specificity, 0.77-0.83) than B-MYB. Logistic Regression coupled with Likelihood-Ratio Tests confirmed that a highly significant relation links increasing TKTL1/CIP-2a/B-MYB protein levels in twice-positive cervical scrapings to the risk of HR-HPV-driven oncoprogression. Finally, a 3 year clinical follow-up showed that 13 patients (50% of total) of the twice-positive group with biomarker values over OTDs compliantly underwent scheduled colposcopy and biopsy. Of these, 11 (i.e., 84.7%) received a positive histological diagnosis, i.e., CIN1 (n = 5; 38.5%) or CIN2/CIN2+ (n = 6; 46,2%). Therefore, TKTL1/CIP-2a/B-MYB protein levels could objectively predict oncoprogression risk in twice (HR-HPV- and Pap smear)-positive women. Further studies will assess the translatability of these findings into clinical settings.

SUBMITTER: Chiarini A

PROVIDER: S-EPMC6456695 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Over Expressed TKTL1, CIP-2A, and B-MYB Proteins in Uterine Cervix Epithelium Scrapings as Potential Risk Predictive Biomarkers in HR-HPV-Infected LSIL/ASCUS Patients.

Chiarini Anna A Liu Daisong D Rassu Mario M Armato Ubaldo U Eccher Claudio C Dal Prà Ilaria I

Frontiers in oncology 20190403

High oncogenic risk human papillomaviruses (HR-HPVs) promote cervical carcinoma development, the fourth most common feminine cancer. A slow oncodevelopmental phase-defined histopathologically as Cervical Intraepithelial Neoplasia (CIN) grades 1-3, or cytologically as Low- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL)-precedes the malignancy. Cervical carcinoma screenings through HR-HPV genotyping and Pap smears are regularly performed in Western countries. Faulty cytology screeni ...[more]

PMID: 31001477

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Project description:Anogenital cancers are associated with ∼13 carcinogenic human papilloma virus (HPV) types in a broader group that cause cervical intraepithelial neoplasia (CIN). Multiple concurrent cervical HPV infections are common, which complicates the attribution of HPV types to different grades of CIN. Here we report the analysis of HPV genotype patterns in the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study with the use of unsupervised hierarchical clustering. Women who underwent colposcopy at baseline (n = 2,780) were grouped into 20 disease categories based on histology and cytology. Disease groups and HPV genotypes were clustered with the use of complete linkage. Risk of 2-year cumulative CIN3+, viral load, colposcopic impression, and age were compared between disease groups and major clusters. Hierarchical clustering yielded four major disease clusters: cluster 1 included all CIN3 histology with abnormal cytology; cluster 2 included CIN3 histology with normal cytology and combinations with either CIN2 or high-grade squamous intraepithelial lesion cytology; cluster 3 included older women with normal or low-grade histology/cytology and low viral load; and cluster 4 included younger women with low-grade histology/cytology, multiple infections, and the highest viral load. Three major groups of HPV genotypes were identified: group 1 included only HPV16; group 2 included nine carcinogenic types, plus noncarcinogenic HPV53 and HPV66; and group 3 included noncarcinogenic types, plus carcinogenic HPV33 and HPV45. Clustering results suggested that colposcopy missed a prevalent precancer in many women with no biopsy/normal histology and high-grade squamous intraepithelial lesion. This result was confirmed by an elevated 2-year risk of CIN3+ in these groups. Our novel approach to study multiple genotype infections in cervical disease with the use of unsupervised hierarchical clustering can address complex genotype distributions on a population level.

Project description:Objective: According to the 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) recommendations, women with a positive high-risk human papillomavirus (HR-HPV) diagnosis and low-grade cervical intraepithelial lesion (LSIL) cytology result should be referred for further colposcopy examination. However, this strategy results in over-treatment in several cases. In this study, we assessed the performance of extended HR-HPV genotyping in women with a simultaneous positive HR-HPV and LSIL diagnosis with the aim of improving the current triage strategy. Methods: This study was an observational analysis of women from the Fujian Province Cervical Lesion Screening Cohorts (FCLSCs). Women who were HR-HPV-positive and had a cytological examination of LSIL, which were followed up with colposcopy and biopsy, from 2015 to 2018 were included. The study endpoint was defined as the detection of histological cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We combined HR-HPV genotypes according to the prevalence rate in histological CIN2+ and ranked them from high to low to establish HR-HPV genotyping models. Outcomes were assessed with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and colposcopy referral rate. Results: Overall, 56,788 women undergoing preliminary screening for HR-HPV genotyping were included in this study. Among them, 10,499 women positive for HR-HPV underwent a cytology examination, and 902 women with LSIL cytology diagnosed and subsequent biopsy results were included in the final evaluation. Among these patients, 25.1% (226/902) were found to have CIN2+ in histology. HPV-16, -58, -52, -18, -33, and -31 infections were the most common genotypes, and HPV-16, -18, -58, -33, and -31 (odds ratio [OR] = 5.41, 2.98, 1.38, 1.24, and 1.21, respectively) were associated with the potential for histological CIN2+, from the highest to lowest. In the detection of CIN2+ lesions in HR-HPV-positive LSIL women of different HR-HPV genotyping models, the extended HPV 16/18/31/33/52/58 genotyping model was found to have better efficacy with higher sensitivity (92.9%) and NPV (93.0%), but a significantly lower colposcopy referral rate (74.7%) than the ASCCP-recommended HR-HPV non-genotyping model. Conclusion: For HR-HPV-positive women with LSIL, the HPV 16/18/31/33/52/58 genotyping model can serve as an alternative approach to the ASCCP recommendations, potentially reducing the unnecessary colposcopy referral burden in China.

Dataset Information

Over Expressed TKTL1, CIP-2A, and B-MYB Proteins in Uterine Cervix Epithelium Scrapings as Potential Risk Predictive Biomarkers in HR-HPV-Infected LSIL/ASCUS Patients.

Publications

Over Expressed TKTL1, CIP-2A, and B-MYB Proteins in Uterine Cervix Epithelium Scrapings as Potential Risk Predictive Biomarkers in HR-HPV-Infected LSIL/ASCUS Patients.

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