Functional biomarkers in cervical precancer: An overview

Gupta, Nalini; Srinivasan, Radhika; Rajwanshi, Arvind

doi:10.1002/dc.21270

Cited by 29 publications

(19 citation statements)

References 72 publications

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“…Cubilla et al (2011) demonstrated that HR-HPVs were correlated with p16INK4a positivity in ~80% of penile carcinoma cases, and suggested that p16INK4a negativity could indicate the HPV DNA absence or monoviral LR-HPV infection. Gupta et al (2010) showed higher p16INK4a expression in cervical HR-HPV lesions and a weak staining pattern in LR-HPV lesions, consistent with our data (Table 6). In this systematic review, meta-analysis and trails pointed out the difficulty of evaluating the use of p16INK4a immunohistochemistry for cytological and histological samples due to the lack of a standardized methodology.…”

Section: Discussionsupporting

confidence: 92%

High-Risk Human Papillomavirus Infection and P16 Expression in Men With Anogenital Lesions Attending a Dermatology Clinic

Dobao¹,

Afonso²,

Rocha³

et al. 2014

VR&R

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Our study comprises a cases series of 71 men attending a dermatology clinic in Brazil during an 18-month period with anogenital HPV infection. Clinical manifestations, laboratory findings and sociodemographic factors were evaluated. Biopsy samples were subjected to histopathological analysis, generic and type-specific viral identification, and p16 INK4a quantification. The average age at diagnosis was 33 years. We observed little variation in identified viral types (HPVs 6, 11, 16 and 53), despite the inclusion of 16 HIV+ patients. The presence of high-risk HPV was associated with receptive anal sex (p<0.05), lesion malignancy (p<0.01) and p16INK4a expression (p<0.05). HIV+ was correlated with HPV16 infection, presence of perianal lesions and high-grade lesions (p<0.05) diagnosed at a younger mean age than HIV-patients (p<0.05). Our results demonstrate the unequivocal relationship between high-risk HPV infection and the presence of high-grade lesions, HPV 16 tropism in the anal epithelium, and the role of receptive anal sex as a risk factor for development of high-grade anal lesions, that present early in HIV+ men who have sex with men. As the 5 high-grade lesions (1 AINII and 4 AIN III) showed p16INK4a negativity but were related to HPV 16 presence, we believe that p16INK4a is a promising biomarker, but its use remains controversial requiring further research.

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Section: Discussionsupporting

confidence: 92%

High-Risk Human Papillomavirus Infection and P16 Expression in Men With Anogenital Lesions Attending a Dermatology Clinic

Dobao¹,

Afonso²,

Rocha³

et al. 2014

VR&R

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“…Recent studies have suggested that testing the performance of p16 INK4a in combination with other biomarkers could improve its performance (Galgano et al 2010, Gupta et al 2010), but we were unable to assess combinations in this study. Another limitation is that the ROC/AUC values were obtained with a convenience sample, which limits the reproducibility of our findings.…”

Section: Discussionmentioning

confidence: 87%

An evaluation of p16INK4a expression in cervical intraepithelial neoplasia specimens, including women with HIV-1

Nicol

Golub

Silva

et al. 2012

Mem. Inst. Oswaldo Cruz

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Although several studies have evaluated the role of p16INK4a as a diagnostic marker of cervical intraepithelial neoplasia (CIN) and its association with disease progression, studies regarding the role of p16INK4a in human immunodeficiency virus (HIV)-infected patients remain scarce. The present study was designed to determine the potential utility of p16INK4a as a diagnostic marker for CIN and invasive cervical cancer in HIV-positive and negative cervical specimens. An immunohistochemical analysis of p16INK4a was performed in 326 cervical tissue microarray specimens. Performance indicators were calculated and compared using receiving operating characteristics curve (ROC)/area under the curve. In HIV-1-negative women, the percentage of cells that was positive for p16INK4a expression was significantly correlated with the severity of CIN (p < 0.0001). A ROC curve with a cut-off value of 55.28% resulted in a sensitivity of 89%, a specificity of 81%, a positive predictive value of 91% and a negative predictive value of 78%. HIV-seropositive women exhibited decreased expression of p16INK4a in CIN2–3 specimens compared with HIV-negative specimens (p = 0.031). The ROC data underscore the potential utility of p16INK4a under defined conditions as a diagnostic marker for CIN 2–3 staging and invasive cervical cancer. HIV-1 infection, however, is associated with relatively reduced p16INK4a expression in CIN 2–3.

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“…18,19 In our study, the analysis of these biomarkers in biopsy material by immunohistochemistry showed that all were positive in a high proportion of the HSIL lesions, which is consistent with current evidence. 8,16,[20][21][22][23] Nevertheless, immunohistochemistry is not adequate for screening purposes. Finally, immunohistochemistry only analyzes a small area of the lesion, which may not be representative of the whole process that could explain the absence of correlation between the mRNA expression in the liquid-based cytology and the immunohistochemistry staining in the simultaneous biopsy for most of the biomarkers.…”

Section: Discussionmentioning

confidence: 99%

“…28,29 Recently, Bourmenskaya et al 30 have shown that a gradual increase in the expression of proliferation markers and a decrease in the expression of pro-apoptotic human genes, as determined by RT-PCR, were associated with increased risks of carcinogenesis. These authors proposed a quantitative model combining the expression of CDKN2A/p16 and BIRC5, which are associated with adverse prognosis, 31,32 and MKI67, which distinguish SIL from normal or benign reactive cervical lesions, 22 for cervical cancer risk assessment. Our results also indicate that a combination of biomarkers could be an adequate strategy for HSIL detection.…”

Section: Discussionmentioning

confidence: 99%

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

Pino

Svanholm-Barrie²,

Torné

et al. 2015

Modern Pathology

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Several high-risk human papillomavirus (HPV)-induced cell biomarkers have been proposed as possible candidates to identify patients harboring high-grade squamous intraepithelial lesions (HSILs) of the uterine cervix. We aimed to determine the feasibility of the detection of the mRNA of six biomarkers in cervical smear specimens obtained by liquid-based cytology and to evaluate whether this approach might be useful in the identification of patients with HSIL. One-hundred and twenty three women referred to colposcopy in the Hospital Clinic of Barcelona were included in the study. After a thorough study, including Pap test, high-risk HPV testing (Hybrid Capture 2 test), and colposcopy with directed biopsy and/or endocervical curettage, 48 patients were diagnosed with HSIL, whereas 75 were classified as negative (n ¼ 28), or harboring low-grade SIL (n ¼ 47). CDKN2A/p16, BIRC5, MMP9, TOP2A, MCM5, and MKI67 mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction in liquid-based cytology after the Pap test and Hybrid Capture 2 performance. The tissue expression of these biomarkers was analyzed by immunohistochemistry in the biopsy material. One-hundred and thirteen out of 123 (92%) liquid-based cytology yielded adequate material for mRNA analysis. TOP2A was the most sensitive (97%) biomarker for the detection of HSIL and CDKN2A/p16 the most specific (78%). The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 96% (95% confidence interval (CI): 88-99) and a specificity of 71% (95% CI: 55-82). In the immunohistochemistry analysis, all biomarkers showed a high sensitivity but low specificity for HSIL, except CDKN2A/p16 which had a sensitivity of 100% and a specificity of 63%. The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 100% (95% CI: 91-100) and a specificity of 43% (95% CI: 32-55). The detection of mRNA of cell biomarkers in liquid-based cytology material is feasible. The combination TOP2A and CDKN2A/p16 has a good balance between sensitivity and specificity for the detection of women with HSIL. Modern Pathology (2015) 28, 312-320; doi:10.1038/modpathol.2014.106; published online 5 September 2014Screening programs based on cervical cytology (Pap test) have led to a decrease in the incidence and the mortality by cervical cancer. However, the efficacy of cytological screening is hampered by the suboptimal sensitivity and interobserver variability of the conventional Pap test. 1,2 Although the introduction of liquid-based cytology has not led to improvements in terms of relative sensitivity for the detection of cervical cancer precursors, 3 this technique has enabled the use of adjunctive tests that may help to reduce the rate of false-negative cytological results and add objectivity to the classical morphological evaluation.High-risk human papillomaviruses (HPV) are the causative agents of cervical cancer, and high-risk HPV testing has shown to improve the sensitivity of the Pap test to over 95%. 4,5 However, high-risk HPV tests have a lower specificity than...

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Functional biomarkers in cervical precancer: An overview

Cited by 29 publications

References 72 publications

High-Risk Human Papillomavirus Infection and P16 Expression in Men With Anogenital Lesions Attending a Dermatology Clinic

High-Risk Human Papillomavirus Infection and P16 Expression in Men With Anogenital Lesions Attending a Dermatology Clinic

An evaluation of p16INK4a expression in cervical intraepithelial neoplasia specimens, including women with HIV-1

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

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