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Pathology & Oncology Research

, Volume 23, Issue 2, pp 295–305 | Cite as

The Value of a Novel Panel of Cervical Cancer Biomarkers for Triage of HPV Positive Patients and for Detecting Disease Progression

  • Norbert Varga
  • Johanna Mózes
  • Helen Keegan
  • Christine White
  • Lynne Kelly
  • Loretto Pilkington
  • Márta Benczik
  • Schaff Zsuzsanna
  • Gábor Sobel
  • Róbert Koiss
  • Edit Babarczi
  • Miklos Nyíri
  • Laura Kovács
  • Sebe Attila
  • Borbála Kaltenecker
  • Adrienn Géresi
  • Adrienn Kocsis
  • John O’Leary
  • Cara M. Martin
  • Csaba JeneyEmail author
Original Article

Abstract

In the era of primary vaccination against HPV and at the beginning of the low prevalence of cervical lesions, introduction of screening methods that can distinguish between low- and high-grade lesions is necessary in order to maintain the positive predictive value of screening. This case-control study included 562 women who attended cervical screening or were referred for colposcopy and 140 disease free controls, confirmed by histology and/or cytology. The cases were stratified by age. Using routine exfoliated liquid based cytological samples RT-PCR measurements of biomarker genes, high-risk HPV testing and liquid based cytology were performed and used to evaluate different testing protocols including sets of genes/tests with different test cut-offs for the diagnostic panels. Three new panels of cellular biomarkers for improved triage of hrHPV positive women (diagnostic panel) and for prognostic assessment of CIN lesions were proposed. The diagnostic panel (PIK3AP1, TP63 and DSG3) has the potential to distinguish cytologically normal hrHPV+ women from hrHPV+ women with CIN2+. The prognostic gene panels (KRT78, MUC5AC, BPIFB1 and CXCL13, TP63, DSG3) have the ability to differentiate hrHPV+ CIN1 and carcinoma cases. The diagnostic triage panel showed good likelihood ratios for all age groups. The panel showed age-unrelated performance and even better diagnostic value under age 30, a unique feature among the established cervical triage tests. The prognostic gene-panels demonstrated good discriminatory power and oncogenic, anti-oncogenic grouping of genes. The study highlights the potential for the gene expression panels to be used for diagnostic triage and lesion prognostics in cervical cancer screening.

Keywords

Human papillomavirus Cervical neoplasia Case-control study Cellular biomarker, biomarker, cervical cancer, carcinogenesis 

Notes

Acknowledgments

This study was funded by the grant SYSTEMCERV, FP7 SME-targeted Collaborative Project, HEALTH-2012.2.1.2-1 Systems Medicine: SME driven research applying systems biology approaches to address medical and clinical needs (John O’Leary, Cara Martin, Csaba Jeney, Miklós Nyíri), KMR_12-1-2012-0032, Hungarian National Research and Development Fund (Csaba Jeney, Miklós Nyíri), AUTOCAST, FP7 Collaborative project, HEALTH-2007-2.4.1-4 Novel cancer screening methods (John O’Leary, Cara Martin, Csaba Jeney, Miklós Nyíri). The authors acknowledge the contribution from CERVIVA - the Irish Cervical Screening Research Consortium, which is funded by the Health Research Board of Ireland (John O’Leary, Cara Martin).

Compliance with Ethical Standards

Conflict of interest

The corresponding author of this work is the inventor of a pending patent related to this work and Cellcall Ltd. owns this patent.

Funding

This study was funded by the grant SYSTEMCERV, FP7 SME-targeted Collaborative Project, HEALTH-2012.2.1.2–1 Systems Medicine: SME driven research applying systems biology approaches to address medical and clinical needs, KMR_12–1–2012-0032, Hungarian National Research and Development Fund, AUTOCAST, FP7 Collaborative project, HEALTH-2007-2.4.1-4 Novel cancer screening methods. The authors acknowledge the contribution from CERVIVA - the Irish Cervical Screening Research Consortium which is funded by the Health Research Board of Ireland.

Supplementary material

12253_2016_94_MOESM1_ESM.doc (587 kb)
ESM 1 (DOC 587 kb)

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Copyright information

© Arányi Lajos Foundation 2016

Authors and Affiliations

  • Norbert Varga
    • 1
  • Johanna Mózes
    • 1
  • Helen Keegan
    • 2
    • 3
  • Christine White
    • 2
    • 3
  • Lynne Kelly
    • 2
    • 3
  • Loretto Pilkington
    • 2
    • 3
  • Márta Benczik
    • 1
  • Schaff Zsuzsanna
    • 4
  • Gábor Sobel
    • 5
  • Róbert Koiss
    • 6
  • Edit Babarczi
    • 6
  • Miklos Nyíri
    • 1
  • Laura Kovács
    • 1
  • Sebe Attila
    • 7
  • Borbála Kaltenecker
    • 8
  • Adrienn Géresi
    • 1
  • Adrienn Kocsis
    • 1
  • John O’Leary
    • 2
    • 3
  • Cara M. Martin
    • 2
    • 3
  • Csaba Jeney
    • 9
    Email author
  1. 1.CellCall LtdBudapestHungary
  2. 2.Department of Histopathology, School of MedicineTrinity College DublinDublinIreland
  3. 3.Molecular Pathology Laboratory, Department of PathologyCoombe Women and Infants University HospitalDublinIreland
  4. 4.2nd Department of PathologySemmelweis UniversityBudapestHungary
  5. 5.2nd Department of Obstetrics and GynecologySemmelweis UniversityBudapestHungary
  6. 6.Department of Gynecology-OncologyUnited Hospital of St. Stephan and LaszloBudapestHungary
  7. 7.Institute of PathophysiologySemmelweis UniversityBudapestHungary
  8. 8.Genoid LtdBudapestHungary
  9. 9.Department of Medical MicrobiologySemmelweis UniversityBudapestHungary

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