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.
Highlights
Human papillomavirus (HPV) infections drive ∼5% of all human cancers [1]
The present work aimed at assessing the worth of three proteins, i.e., B-MYB, Cancerous Inhibitor of phosphatase 2A (PP2A) (CIP-2a), and TKTL1, as risk predictive biomarkers of high-risk HPV (HR-HPV)-driven precancerous disease progression
“Twice-negative” specimens served as controls
Summary
Human papillomavirus (HPV) infections drive ∼5% of all human cancers [1]. So far, DNA sequence information has identified more than 200 HPV genotypes [2,3,4]. Human cervical carcinoma is the fourth most common female cancer worldwide [11, 15] These malignancies are generally preceded by a preinvasive or in situ disease, defined (i) via histopathological criteria as Cervical Intraepithelial Neoplasia (CIN), distinguished in three sequential grades, i.e., CIN1, CIN2, and CIN3; and (ii) via cytological criteria as Low-grade- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL, respectively) or as Atypical Squamous Lesions of Undetermined Significance (ASCUS) [14, 16]. A discrete fraction of noncompliant patients drops from any proposed follow-up program [21, 22] It should be the first choice when patient’s compliance is uncertain, direct colposcopy referral for all LSIL/ASCUS cases would mostly detect only minor dysplasia [23]. Present genotyping does not cover oncogenic l-HRand LR-HPV subtypes
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