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ResearchMedical oncology
University Medical Center Groningen

PI: G. Bea A. Wisman, PhD

B. Wisman

Position: PI
Contact: email
Phone number: +31 (0)50 361 9554
Publications: Pubmed

Biography

Bea Wisman is a molecular biologist and obtained her PhD at the Departments of Medical Oncology and Gynecologic Oncology, University Medical Center Groningen in the laboratory of Prof dr EGE de Vries. The main subject of her PhD was to study the role of telomerase in human diseases with an emphasis on gynecological cancers. During her PhD, she received a KWF travel grant to perform research at the Beatson Institute (Glasgow, UK) in the lab of Dr. N. Keith. After her PhD, she remained interested in translational research and obtained a post-doc position in the Department of Gynecologic Oncology (head: Prof. AGJ van der Zee) and performed research on ovarian cancer and cervical cancer. In 2005, she became project leader in the lab of Prof. AGJ van der Zee. Over the last years, studies have been performed on the detection and (prognostic) significance of cell biological parameters in gynecologic cancers with a special interest in epigenetics. In 2004, she was a visiting scientist in the lab of Prof. D Sidransky (Johns Hopkins University School of Medicine, Baltimore, USA).

Research

1. Improvement of the current population-based cervical cancer screening

Cervical cancer is an important cause of death in women worldwide. Cervical carcinogenesis is highly associated with high-risk human papillomavirus (hr-HPV) infections. Cytomorphological examination of cervical smears is a widely applied, though not ideal screening method for cervical cancer and its precursors (cervical intraepithelial neoplasia (CIN), because of its non-optimal sensitivity. Hr-HPV testing has been suggested to improve cervical cancer screening. However, the specificity of hr-HPV testing, especially in a young screening population is relatively low. Additional objective markers are needed to improve sensitivity and specificity for cervical cancer screening. Methylation of tumor suppressor genes contributes to an immortalized phenotype by silencing expression of genes responsible for control of normal cell differentiation and/or inhibition of cell growth. In addition to the functional implications of gene inactivation in tumor development, these methylation patterns represent excellent targets for novel diagnostic approaches based on methylation sensitive PCR (MSP). Promoter hypermethylation analysis might improve sensitivity and specificity for cervical cancer screening. We search for specific and sensitive methylation markers by several genome-wide approaches resulting in the identification of a methylation panel of genes, which will improve population-based cervical cancer screening. In addition, the role of these genes in cervical carcinogenesis is analyzed.

Cervical Carcinogenesis
Figure 1. Schematic model of the main important biological steps in cervical carcinogenesis (abbreviations used: HPV: human papillomavirus, DNMT1: DNA methyltransferase 1, TSG: tumor suppressor genes).

2. Identification of novel genes and pathways in the response to therapy

The response to chemotherapy (in ovarian cancer) and chemoradiation (in cervical cancer) is mainly determined by genes belonging to pathways involved in cell cycle, DNA repair and apoptosis. Silencing of tumor suppressor genes by hypermethylation of CpG islands in promoter regions of these genes is a common feature of human cancer. By the analysis of protein expression and DNA promoter hypermethylation on patient samples and cancer cell lines, genes and/or pathways will be identified and validated by their relation in the response to chemotherapy or chemoradiation. Ultimately, we will modulate these genes/pathways in order to improve the response on therapy.

Research is performed in collaboration with groups within the department and institute (UMCG/RUG) as well as in national and international settings. Funding has been obtained from the Dutch Cancer Society and OncoMethylome Sciences, S.A. Liege, Belgium.

Group members

  • Nicolette Alkema - MD/PhD student
  • Joost Caumanns - PhD student
  • Roland van Leeuwen - PhD student
  • Tushar Tomar - PhD student
  • Harry Klip - Technician
  • Gert Jan Meersma - Technician

Selected publications

  • Huisman C, van der Wijst MG, Falahi F, Overkamp J, Karsten G, Terpstra MM, Kok M, van der Zee AG, Schuuring E, Rots MG, Wisman GB. Prolonged re-expression of the hypermethylated gene EPB41L3 using artifical transcription factors and epigenetic drugs. Epigenetics. 2015. [Epub ahead of print]
  • Boers A, Wang R, Slagter-Menkema L, van Hemel BM, Ghyssaert H, van der Zee AG, Wisman GB, Schuuring E. Clinical validation of the Cervista HPV HR test according to the international guidelines for human papillomavirus test requirements for cervical cancer screening. J Clin Microbiol. 52:4391-3, 2015.
  • Boers A, Bosgraaf RP, van Leeuwen RW, Schuuring E, Heideman DA, Massuger LF, Verhoef VM, Buiten J, Melchers WJ, van der Zee AG, Bekkers RL, Wisman GB. DNA methylation analysis in self-sampled brush materials as a triage test in hrHPV-positive women. Br J Cancer. 111:1095-101, 2014.
  • Alkema NG, Tomar T, van der Zee AG, Everts M, Meersma GJ, Hollema H, de Jong S, van Vugt MA, Wisman GB. Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous ovarian cancer. Gynecol Oncol. 133:591-8, 2014.
  • Brait M, Maldonado L, Noordhuis MG, Begum S, Loyo M, Poeta ML, Barbosa A, Fazio VM, Angioli R, Rabitti C, Marchioni L, de Graeff P, van der Zee AG, Wisman GB, Sidransky D, Hoque MO. Assocaiation of premotor methylation of VGF and PGP9.5 with ovarian cancer progression. PLos One. 8:e70878, 2013.
  • Huisman C, Wisman GB, Kazemier HG, van Vugt MA, van der Zee AG, Schuuring E, Rots MG. Functional validation of putative tumor suppressor gene C13ORF18 in cervical cancer by Artificial Transcription Factors. Mol Oncol. 7:669-79, 2013.
  • Bierkens M, Hesselink AT, Meijer CJ, Heideman DA, Wisman GB, van der Zee AG, Snijders PJ, Steenbergen RD. CADM1 and MAL promotor methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease. Int J Cancer. 133:1293-9, 2013.
  • Lendvai A, Johannes F, Grimm C, Eijsink JJ, Wardenaar R, Volders HH, Klip HG, Hollema H, Jansen RC, Schuuring E, Wisman GB, van der Zee AG. Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia. Epigenetics. 7:1268-78, 2012.
  • Roossink F, de Jong S, Wisman GB, van der Zee AG, Schuuring E. DNA hypermethylation biomarkers to predict reponse to cisplatin treatment, radiotherapy or chemoradiation: the present state of art. Cell Oncol. 35:231-41, 2012.
  • Roossink F, Wieringa HW, Noordhuis MG, ten Hoor KA, Kok M, Slagter-Menkema L, Hollema H, de Bock GH, Pras E, de Vries EG, de Jong S, van der Zee AG, Schuuring E, Wisman GB, van Vugt MA. The role of ATM and 53BP1 as predictive markers in cervical cancer. Int J Cancer. 131:2056-66, 2012.
  • Eijsink JJ, Lendvai A, Deregowski V, Klip HG, Verpooten G, Dehaspe L, de Bock GH, Hollema H, van Criekinge W, Schuuring E, van der Zee AG, Wisman GB. A four-gene methylation marker panel as triage test in high-risk human papillomavirus positive patients. Int J Cancer. 130:1851-9, 2012.
  • Noordhuis MG, Fehrmann RS, Wisman GB, Bijhuis ER, van Zanden JJ, Moerland PD, ver Loren van Themaat E, Volders HH, Kok M, ten Hoor KA, Hollema H, de Vries EG, de Bock GH, van der Zee AG, Schuuring E. Involvement of the TGF-beta and beta-catenin pathways in pelvic node metastasis in early-stage cervical cancer. Clin Cancer Res. 17:1317-30, 2011.
  • Noordhuis MG, Eijsink JJ, Roossink Fm de Graeff P, Pras E, Schuuring E, Wisman GB, de Bock GH, van der Zee AG. Prognostic cell biological markers in cervical cancer patients primarily treated with (chemo)radiation: a systemic review. Int J Radiat Oncol Biol Phys. 79:325-34, 2011.
  • Eijsink JJ, Yang N, Lendvai A, Klip HG, Volders HH, Buikema HJ, van Hemel BM, Voll M, Coelingh Bennink HJ, Schuuring E, Wisman GB, van der Zee AG. Detection of cervical neoplasia by DNA methylation analysis in cervico-vaginal lavages, a feasibility study. Gynecol Oncol. 120:280-3, 2011.
  • Noordhuis MG, Eijsink JJ, ten Hoor KA, Roossink F, Hollema H, Arts HJ, Pras E, Maduro JH, Reyners AK, de Bock GH, Wisman GB, Schuuring E, van der Zee AG. Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer. Clin Cancer Res. 15:7389-97, 2009.
  • Yang N, Eijsink JJ, Lendvai A, Volders HH, Klip H, Buikema HJ, van Hemel BM, Schuuring E, van der Zee AG, Wisman GB. Methylation markers for CCNA1 and C13ORF18 are strongly associated with high-grade cervical intraepithelial neoplasia and cervical cancer in cervical scrapings. Cancer Epidemiol Biomarkers Prev. 18:3000-7, 2009.
  • de Graeff P, Crijns APG, ten Hoor KA, Klip HG, Hollema H, Oien K, Bartlett JM, Wisman GB, de Bock GH, de Vries EG, de Jong S, van der Zee AG. The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer. Br J Cancer. 99:341-9, 2008.
  • Wisman GB, Hoque MO, Kim MS, Ostrow KL, Liu J, Park HL, Poeta ML, Jeronimo C, Henrique R, Lendvai A, Schuuring E, Begum S, Rosenbaum E, Ongenaert M, Yamashita K, Califano J, Westra W, van der Zee AG, van Criekinge W, Sidransky D. Genome-wide promoter analysis uncovers portions of the cancer methylome. Cancer Res. 68:2661-70, 2008.
  • Wisman GB , Nijhuis ER, Hoque MO, Reesink-Peters N, Koning AJ, Volders HH, Buikema HJ, , Boezen HM, Hollema H, Schuuring E, Sidransky D, van der Zee AG. Assessment of gene promoter hypermethylation for detection of cervical neoplasia. Int J Cancer. 119:1908-14, 2006.
  • Schröder CP, Wisman GB, de Jong S, van der Graaf WT, Ruiters MH, Mulder NH, de Leij LF, van der Zee AG, de Vries EG. Telomere length in breast cancer patients before and after chemotherapy with or without stemm cell tranplantation. Br J Cancer.84:1348-53, 2001.
  • Hoare SF, Bryce LA, Wisman GB, Burns S, Going JJ, van der Zee AG, Keith WN. Lack of telomerase RNA gene expression in ALT cells is associated with methylation of the hTERC promoter. Cancer Res. 61:27-32, 2001.
  • Wolthers KC, Otto SA, Wisman GB, Fleury S, Reiss P, ten Kate RW, van der Zee AG, Miedema F. Normal T-cell telomerase activity and upregulation in human immunodeficiency virus-1 infection. Blood. 93:1011-9, 1999.
  • Wisman GB , Hollema H, de Jong S, ter Schegget J, Tjong-A-Hung SP, Ruiters MHJ, Krans M, de Vries EG, van der Zee AG. Telomerase activity as a biomarker for (pre)neoplastic cervical disease in scrapings and frozen sections from patients with abnormal cervical smear. J Clin Oncol. 16:2238-45, 1998.
  • Wolthers KC, Wisman GB, Otto SA, de Roda Husman AM, Schaft N, de Wolf F, Goudsmit J, Coutinho RA, van der Zee AG, Meyaard L, Miedema F. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science. 274:1543-7, 1996.
  • ·       Wisman GB , Hollema H, de Jong S, ter Schegget J, Tjong-A-Hung SP, Ruiters MHJ, Krans M, de Vries EG, van der Zee AG. Telomerase activity as a biomarker for (pre)neoplastic cervical disease in scrapings and frozen sections from patients with abnormal cervical smear. J Clin Oncol. 16:2238‑45, 1998.

Last modified:15 September 2015 09.30 a.m.