Use of Cytology, E6/E7 mRNA, and p16<sup>INK4a</sup>–Ki-67 to Define the Management of Human Papillomavirus (HPV)–Positive Women in Cervical Cancer Screening

Gustinucci, Daniela; Rossi, Paolo Giorgi; Cesarini, Elena Nardi; Broccolini, Massimo; Bulletti, Simonetta; Carlani, Angela; D’Angelo, Valentina; D’Amico, Maria Rosaria; Dato, Eugenio Di; Galeazzi, Paola; Malaspina, Morena; Martinelli, Nadia; Spita, Nicoletta; Tintori, Beatrice; Giaimo, Maria Donata; Passamonti, Basilio

doi:10.1093/ajcp/aqv019

Cited by 53 publications

(46 citation statements)

References 43 publications

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“…Cervical cytology immunocytochemistry with "dual staining" (p16 plus Ki-67) could, therefore, be used as a triage for HPV-positive women with mildly abnormal smear results [13,20,[23][24][25][26][27][28][29][30][31][32][33]. This dual biomarker approach is morphology independent [27,34] and, therefore, has good reproducibility [34].…”

mentioning

confidence: 99%

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

et al. 2018

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Objective: Our objective was to verify the sensitivity and specificity of dual immunocytochemistry staining for p16 and Ki-67 in liquid-based samples (the “dual” assay) for cervical lesion screening, compared to biopsy findings and human papillomavirus (HPV) DNA molecular detection. Study Design: Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for the “dual immunocytochemistry assay” were calculated and compared to histopathological results and to high-risk HPV DNA detection in adult women or teenagers submitted to cervical cancer screening. Results: A total of 151 women were included. The majority (96.2%) of those with negative dual assay results had lower biopsy grades (p < 0.001). Women with cytology results suggestive of cervical cancer had positive dual immunocytochemistry assay results more frequently (p < 0.001), and these positive results were also significantly associated with biopsy findings (p < 0.001) and with high-risk genotype HPV infection (p = 0.007). Specificity and PPV for the dual assay were 0.972 (0.855–0.999) and 0.800 (0.284–0.995), respectively, and 1.000 (0.590–1.000) and 1.000 (0.631–1.000) for HPV detection. Conclusions: The dual immunocytochemistry assay had high specificity and PPV. It reveals a persistent HPV infection, avoiding the need for new tissue collections for biopsies or hybrid capture.

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mentioning

confidence: 99%

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

et al. 2018

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“…p16INK4a is a cyclin-dependent kinase inhibitor that decelerates the cell cycle and functions as a tumor-suppressor gene [34] in many human cancers, in contrast, overexpression of p16INK4a in the nucleus and the cytoplasm strongly correlates with cancer progression in cervical squamous cell carcinomas [35,36]. Therefore, the combined detection of the E6/E7 mRNA and p16INK4a protein is a useful biomarker for histological diagnosis and evaluating of clinical prognosis [34,37,38,39,40,41]. MiR-331-3p has been thought one of cancer-associated miRNAs.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-331-3p Suppresses Cervical Cancer Cell Proliferation and E6/E7 Expression by Targeting NRP2

Fujii

Shimada

Asano

et al. 2016

IJMS

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Aberrant expression of microRNAs (miRNAs) is involved in the development and progression of various types of cancers. In this study, we investigated the role of miR-331-3p in cell proliferation and the expression of keratinocyte differentiation markers of uterine cervical cancer cells. Moreover, we evaluated whether neuropilin 2 (NRP2) are putative target molecules that regulate the human papillomavirus (HPV) related oncoproteins E6 and E7. Cell proliferation in the human cervical cancer cell lines SKG-II, HCS-2, and HeLa was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Cellular apoptosis was measured using the TdT-mediated dUTP nick end labeling (TUNEL) and Annexin V assays. Quantitative RT-PCR was used to measure the messenger RNA (mRNA) expression of the NRP2, E6, E7, p63, and involucrin (IVL) genes. A functional assay for cell growth was performed using cell cycle analyses. Overexpression of miR-331-3p inhibited cell proliferation, and induced G2/M phase arrest and apoptosis in SKG-II, HCS-2 and HeLa cells. The luciferase reporter assay of the NRP2 3′-untranslated region revealed the direct regulation of NRP2 by miR-331-3p. Gene expression analyses using quantitative RT-PCR in SKG-II, HCS-2, and HeLa cells overexpressing miR-331-3p or suppressing NRP2 revealed down-regulation of E6, E7, and p63 mRNA and up-regulation of IVL mRNA. Moreover, miR-331-3p overexpression was suppressed NRP2 expression in protein level. We showed that miR-331-3p and NRP2 were key effectors of cell proliferation by regulating the cell cycle, apoptosis. NRP-2 also regulates the expression of E6/E7 and keratinocyte differentiation markers. Our findings suggest that miR-331-3p has an important role in regulating cervical cancer cell proliferation, and that miR-331-3p may contribute to keratinocyte differentiation through NRP2 suppression. miR-331-3p and NRP2 may contribute to anti-cancer effects.

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“…The simultaneous expression of p16 and Ki-67 in one cell is indicative for cell cycle dysregulation and appears indicative for a transforming hrHPV infection [61][62][63][64]. Three recent studies have addressed the performance of p16/Ki-67 dualstained cytology for triage of hrHPV-positive women, in population-based screening cohorts (n = 1509 [65] and n = 396 [66]) and a gynecologic outpatient population (n = 446 [67]). In these studies, p16/Ki-67 dual-stained cytology had a consistently high sensitivity for ≥CIN3 (86.9-93.8% which was comparable to that of Pap cytology [65][66][67].…”

Section: P16/ki-67 Dual-stained Cytologymentioning

confidence: 99%

“…Three recent studies have addressed the performance of p16/Ki-67 dualstained cytology for triage of hrHPV-positive women, in population-based screening cohorts (n = 1509 [65] and n = 396 [66]) and a gynecologic outpatient population (n = 446 [67]). In these studies, p16/Ki-67 dual-stained cytology had a consistently high sensitivity for ≥CIN3 (86.9-93.8% which was comparable to that of Pap cytology [65][66][67]. The specificity for ≥CIN3 of p16/Ki-67 dual-stained cytology was estimated at 51.2% [67] to 56.9% [65], which is high compared to Pap cytology (44.9% [67] to 48.7% [65]).…”

Section: P16/ki-67 Dual-stained Cytologymentioning

confidence: 99%

“…For example, the detection of specific microRNAs has shown promising results in one clinical study [109]. Furthermore, detection of the E6 protein [110,111], and E6/ E7 mRNA [66,[112][113][114] was evaluated in some clinical cohorts of hrHPV-positive women, however with disappointing results. These assays require a relatively complex genotype-specific approach and have not been shown to reach the desired NPV in hrHPV-positive women; others did not reach the required phase of marker validation and are therefore beyond the scope of this review [42,43].…”

Section: Combining Host Cell Dna Methylation Analysis With Other Markmentioning

confidence: 99%

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Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Luttmer

Strooper

Steenbergen

et al. 2016

Expert Review of Molecular Diagnostics

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Introduction: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. Areas covered: Many different colposcopy triage strategies, comprising both microscopy-based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (≥100 hrHPV-positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. ARTICLE HISTORY

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Use of Cytology, E6/E7 mRNA, and p16^INK4a–Ki-67 to Define the Management of Human Papillomavirus (HPV)–Positive Women in Cervical Cancer Screening

Abstract: The high sensitivity of combined strategies probably allows longer intervals in HPV-positive, triage-negative women.

Cited by 53 publications

References 43 publications

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

MicroRNA-331-3p Suppresses Cervical Cancer Cell Proliferation and E6/E7 Expression by Targeting NRP2

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

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Use of Cytology, E6/E7 mRNA, and p16INK4a–Ki-67 to Define the Management of Human Papillomavirus (HPV)–Positive Women in Cervical Cancer Screening

Abstract: The high sensitivity of combined strategies probably allows longer intervals in HPV-positive, triage-negative women.

Cited by 53 publications

References 43 publications

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

Dual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study

MicroRNA-331-3p Suppresses Cervical Cancer Cell Proliferation and E6/E7 Expression by Targeting NRP2

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

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Use of Cytology, E6/E7 mRNA, and p16^INK4a–Ki-67 to Define the Management of Human Papillomavirus (HPV)–Positive Women in Cervical Cancer Screening