TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions

BMC Cancer. 2021 Jan 7;21(1):39. doi: 10.1186/s12885-020-07740-1.

Abstract

Background: To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer.

Methods: We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit.

Results: We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%).

Conclusions: We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.

Keywords: Biomarkers; Cervical cancer; Cyclin E1; HPV; SIL; TOP2A/MCM2; p16INK4a.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / metabolism
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Cytodiagnosis / methods
  • DNA Topoisomerases, Type II / metabolism*
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Liquid Biopsy / methods*
  • Middle Aged
  • Minichromosome Maintenance Complex Component 2 / metabolism*
  • Oncogene Proteins / metabolism*
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / virology
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology*
  • Precancerous Conditions / surgery
  • Precancerous Conditions / virology
  • Prognosis
  • Uterine Cervical Dysplasia / metabolism
  • Uterine Cervical Dysplasia / pathology
  • Uterine Cervical Dysplasia / surgery
  • Uterine Cervical Dysplasia / virology
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / surgery
  • Uterine Cervical Neoplasms / virology

Substances

  • Biomarkers, Tumor
  • CCNE1 protein, human
  • CDKN2A protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p16
  • Oncogene Proteins
  • Poly-ADP-Ribose Binding Proteins
  • MCM2 protein, human
  • Minichromosome Maintenance Complex Component 2
  • DNA Topoisomerases, Type II
  • TOP2A protein, human

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