Introduction of p16INK4a as a surrogate biomarker for HPV in women with invasive cervical cancer in Sudan

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Abstract

Background

Cervical cancer is the fourth most common cancer in women worldwide with highest incidence reported in Eastern Africa in 2012. The primary goal of this study was to study the expression of p16 ^INK4a in squamous cell carcinoma (SCC) of the cervix by immunohistochemistry (IHC) and determine relation with clinico-pathological parameters. This study further explored the correlation of p16 ^INK4a immunostaining with another proliferation marker, Ki-67 and to study if human papillomavirus (HPV) IHC can be used as a marker for detection of virus in high-grade dysplasia.

Methods

A total of 90 samples, diagnosed for cervical cancer, were included in the study. Fixed Paraffin Embedded (FFPE) tissue sections were stained with anti-p16 ^INK4a, anti-Ki-67 and anti-HPV antibodies using automated immunohistochemistry platform (ASLink 48-DAKO).

Results

Immunohistochemical protein expression of p16 ^INK4a positivity was found to be highest in SCC (92.2%, n = 71) than other HPV tumors (76.9%, n = 10). The majority of cases (97.4%) were p16 ^INK4a positive in the age group 41–60 years. In addition, a statistically significant difference between p16 ^INK4a and HPV was observed among total cervical tumor cases and SCC cases.

Conclusions

As expected staining of invasive cervical cancer with anti-HPV showed rare positivity because HPV heralds active infection in dysplastic lesions and not of frank cervical carcinoma. In contrast, anti-p16 ^INK4a IHC results showed positive correlation in SCC and other cervical tumors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13027-017-0159-0) contains supplementary material, which is available to authorized users.

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Most cited references 37

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Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions.

Renske Steenbergen, Chris J. L. M. Meijer, Peter J. F. Snijders … (2014)

Infection of cervical epithelium with high-risk human papilloma virus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN) lesions, the morphology of which can overlap. In transforming CIN lesions, aberrations in host cell genes accumulate over time, which is necessary for the ultimate progression to cancer. On the basis of (epi)genetic changes, early and advanced transforming CIN lesions can be distinguished. This paves the way for new molecular tools for cervical screening, diagnosis and management of cervical cancer precursor lesions.

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Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri.

R Klaes, Ruediger Ridder, T. Friedrich … (2001)

Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through high-risk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16(INK4a). Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16(INK4a). In line with this hypothesis, we observed marked overexpression of p16(INK4a) in all cervical intraepithelial neoplasm (CIN) I lesions (n = 47) except those associated with low-risk HPV types (n = 7), all CIN II lesions (n = 32), all CIN III lesions (n = 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16(INK4a) was observed in normal cervical epithelium (n = 42), inflammatory lesions (n = 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n = 7). Dysplastic cells could also be identified in cervical smears using a specific p16(INK4a) monoclonal antibody. These data demonstrate that p16(INK4a) is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears. Copyright 2001 Wiley-Liss, Inc.

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Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming.

Christopher Crum, Robert McLaughlin, Karl Munger (2011)

Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16(INK4A). Moreover, KDM6A- and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance.

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Author and article information

Contributors

Hina Sarwath: his2014@qatar-med.cornell.edu

Devendra Bansal: dbansal2006@gmail.com

Nazik Elmalaika Husain: nazikhusain@gmail.com

Mahmoud Mohamed: MMOHD13@hamad.qa

Ali A. Sultan: als2026@qatar-med.cornell.edu

Shahinaz Bedri: +974-4492-8387 , shahinazbedri@gmail.com , shb2026@qatar-med.cornell.edu

Journal

Journal ID (nlm-ta): Infect Agent Cancer

Journal ID (iso-abbrev): Infect. Agents Cancer

Title: Infectious Agents and Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-9378

Publication date (Electronic): 30 September 2017

Publication date PMC-release: 30 September 2017

Publication date Collection: 2017

Volume: 12

Electronic Location Identifier: 50

Affiliations

[1 ]ISNI 0000 0001 0516 2170, GRID grid.418818.c, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine – Qatar, , Cornell University, Qatar Foundation - Education City, ; Doha, Qatar

[2 ]ISNI 0000 0001 0516 2170, GRID grid.418818.c, Department of Microbiology and Immunology, Weill Cornell Medicine – Qatar, , Cornell University, Qatar Foundation - Education City, ; Doha, Qatar

[3 ]GRID grid.442422.6, Faculty of Medicine, Omdurman Islamic University, ; P.O. Box 382, Omdurman, Sudan

Article

Publisher ID: 159

DOI: 10.1186/s13027-017-0159-0

PMC ID: 5622439

PubMed ID: 29021820

SO-VID: 66f2b64a-44bb-4f1f-8a74-5f8b831611db

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 June 2017

Date accepted : 8 September 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100008982, Qatar National Research Fund;

Award ID: NPRP-5-098-3-021

Award Recipient : Ali A. Sultan

Funded by: Will Cornell Medicine-Qatar

Award ID: BMRP-5726005905

Award Recipient : Shahinaz Bedri

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cervical cancer,human papillomavirus,p16ink4a,ki-67,immunohistochemistry,sudan

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cervical cancer, human papillomavirus, p16ink4a, ki-67, immunohistochemistry, sudan