Molecular Cell Biology

Molecular and cell biology of cervical (pre)malignancies

Aim

The research focusses on unravelling of the molecular processes during the development of the (pre)malignant stages of cervical cancer. These processes include the initial steps during cervical carcinogenesis, in particular the study of the progenitor cell that is targeted by the Human Papilloma Virus (HPV). Furthermore, questions with respect to the different types of stem cell populations in the ecto- and endo cervix are being addressed by means of specific immunomarkers. In doing so, the molecular processes involved in the development of premalignant lesions into an invasive carcinoma can be monitored.

Since we have shown that integration of the virus into the host genome can affect the progression of cervical premalignancies, advanced molecular protocols are being developed to detect HPV subtypes and their physical status. These techniques include the Multiplex Ligation-dependent  Probe Amplification (MLPA) and Single tube Multiplex Amplification in  Real Time (SMART). To detect the genomic instability during  progression of the lesions, fluorescent in situ hybridization protocols have been developed and optimized. These assays allow the detection of chromosomal aberrations and can distinguish between the episomal and integrated physical status of the virus. Improved immunocytochemical techniques have been developed for the sensitive and reproducible detection of proliferation and differentiation markers, such as different keratins and SOX transcription factors. Finally more recent studies have focussed on methylation of specific genes involved in the cervical carcinogenesis.

Key publications

  1. Hopman A.H.N., Ramaekers F.C.S.: Development of the uterine cervix; and its implications for the pathogenesis of cervical cancer. In: Essentials of diagnostic gynecological pathology. Pathology of the cervix (S. Herrington) Springer 2017, in press.
  2. Koeneman MM, Kruse AJ, Kooreman LF, Zur Hausen A, Hopman AH, Sep SJ, Van Gorp T, Slangen BF, van Beekhuizen HJ, van de Sande M, Gerestein CG, Nijman HW, Kruitwagen RF. OPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 2016, 20;16:132.
  3. Ossel J, Litjens RJ, Reijans M, Brink AA, Ummelen M, Ramaekers FC, Hopman AH, Simons G. Human papillomavirus typing by single tube multiplex amplification in real time (SMART): the PapillomaFinder® SMART 20 assay. J Clin Virol. 2014, 61:540-7
  4. Bergshoeff VE, Van der Heijden SJ, Haesevoets A, Litjens SG, Bot FJ, Voogd AC, Chenault MN,Hopman AH, Schuuring E, Van der Wal JM, Manni JJ, Ramaekers FC, Kremer B, Speel EJ. Chromosome instability predicts progression of premalignant lesions of the larynx. Pathology. 2014, 46:216-24
  5. Litjens RJ, Van de Vijver KK, Hopman AH, Ummelen MI, Speel EJ, Sastrowijoto SH, Van Gorp T, Slangen BF, Kruitwagen RF, Krüse AJ. The majority of metachronous CIN1 and CIN3 lesions are caused by different human papillomavirus genotypes, indicating that the presence of CIN1 seems not to determine the risk for subsequent detection of CIN3. Hum Pathol. 2014, 45:221-6
  6. Theelen W, Litjens RJ, Vinokurova S, Haesevoets A, Reijans M, Simons G, Smedts F, Herrington CS, Ramaekers FC, von Knebel Doeberitz M, Speel EJ, Hopman AH. Human papillomavirus multiplex ligation-dependent probe amplification assay for the assessment of viral load, integration, and gain of telomerase-related genes in cervical malignancies.Hum Pathol. 2013, 44:2410-8
  7. Litjens RJ, Theelen W, van de Pas Y, Ossel J, Reijans M, Simons G, Speel EJ, Slangen BF, Ramaekers FC, Kruitwagen RF, Hopman AH. Use of the HPV MLPA assay in cervical cytology for the prediction of high grade lesions. J Med Virol. 2013, 85:1386-93
  8. Litjens RJ, Hopman AH, van de Vijver KK, Ramaekers FC, Kruitwagen RF, Kruse AJ. Molecular biomarkers in cervical cancer diagnosis: a critical appraisal.Expert Opin Med Diagn. 2013, 7:365-77
  9. Mooren JJ, Kremer B, Claessen SM, Voogd AC, Bot FJ, Peter Klussmann J, Huebbers CU, Hopman AH, Ramaekers FC, Speel EJ. Chromosome stability in tonsillar squamous cell carcinoma is associated with HPV16 integration and indicates a favorable prognosis. Int J Cancer. 2013, 15;1781-9
  10. Theelen W, Speel EJ, Herfs M, Reijans M, Simons G, Meulemans EV, Baldewijns MM, Ramaekers FC, Somja J, Delvenne P, Hopman AH. Increase in viral load, viral integration, and gain of telomerase genes during uterine cervical carcinogenesis can be simultaneously assessed by the HPV 16/18 MLPA-assay. Am J Pathol. 2010, 177:2022-33
  11. Smedts F, Ramaekers FC, Hopman AH. The two faces of cervical adenocarcinoma in situ. Int J Gynecol Pathol. 2010, 29:378-85

Team leader

Ton Hopman, PhD
T: (+31) (0)43 3881358
E: hopman@maastrichtuniversity.nl

Research group

Research technicians: Mieke Henfling, Monique Ummelen

School

GROW