The research of this group is composed of two main themes:
1)
Epigenetic-, Genetic and Expression Profiling of colorectal, ovarian, renal cell and breast cancer, to obtain novel insights in cancer biology and discover diagnostic and prognostic markers.
Re-expression micro-array techniques, using cell lines from colorectal, ovarian an renal cell cancer are used to find candidate tumour suppressor genes, which have been epigenetically silenced by DNA promoter hypermethylation. This has resulted in a sensitive and specific panel of biomarkers for colorectal cancer (CRC), which will be tested in blood and faeces from individuals participating in several national (co-operation with a.o. the VUMC in Amsterdam) and international prospective screening projects. One of these is a local CRC screening project organised by the Dept. of Gastroenterology of the University Hospital Maastricht, performed among employees of several companies in the area of Southern Limburg, and was started in the second half of 2006.
Epigenetically silenced genes are studied for their role in differentiating between serous borderline tumours and serous carcinomas of the ovary, whereas the profile of epigenetically silenced genes in renal cell cancer is being correlated with genetic changes in this tumour type (notably VHL mutations) and with downstream effects along the HIF oncogenic pathway.
A potential role of DNA promoter hypermethylation in the development of breast cancer is studied in normal mammary epithelium, in situ carcinoma and invasive cancers.
The work within this theme will most likely be extended to skin and lung cancer.
2)
Molecular epidemiologic studies on the role of dietary factors in colorectal cancer carcinogenesis.
In a succesful co-operation with the department of Epidemiology (Prof.dr. Piet van den Brandt, Dr. Matty Weijenberg), the relation between (epi-)genetic alterations and dietary factors in a series of approximately 800 CRC patients derived from the Netherlands Cohort Study (NLCS) is studied. Currently, the following questions are addressed:
-Whether promoter methylation of the caretaker genes O6-MGMT, MBD4 and hMLH1 leads to specific alterations in the gatekeeper genes K-ras, APC and ?-catenin and MSI.
-Whether dietary intake of components which provide (folate, vitamins B6 and B12) or degrade (alcohol) methyl donors is associated with promoter methylation of O6-MGMT and hMLH1.
-Whether the effect of methyl donor intake on promoter methylation is modified by single nucleotide poly-morphisms (SNPs) in genes involved in methyl donor metabolism, i.e. 5-10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR).
This work will provide new insights in the relationship between promoter methylation of caretaker genes and the occurrence of specific genetic alterations in gatekeeper genes involved in CRC carcinogenesis. In addition, the role of dietary intake of methyl donor providers and -degraders and genetic susceptibility, represented by SNPs in genes involved in methyl donor metabolism, on promoter methylation of caretaker genes is clarified.
This might lead to rational dietary interventions, based on the genetic composition of an individual.
Figure: SNP analysis for methyl donor metabolising enzymes in colorectal cancer
Ongoing funding (type of financing)
Transnational University Limburg (1st )
ZON Mw (2nd)
SenterNovem (2nd)
Dutch Cancer Society (3rd)
Oncomethylome Sciences (4th)
Selected publications
Derks S, Postma C, Moerkerk PT, Bosch van den SM, Carvalho B, Hermsen MA, Giaretti W, Herman JG, Weijenberg MP, Bruïne de AP, Meijer GA, Engeland van M.
Promoter methylation precedes chromosomal alterations in colorectal cancer development.
Cell Oncol 2006; 28(5-6): 247-257
Sieben NL, Roemen GH, Oosting J, Fleuren GJ, Engeland van M, Prat J.
Clonal analysis favors a monoclonal origin for serous borderline tumours with peritoneal implants.
J Pathol 2006; 210(4): 405-411
Vogel de S, Engeland van M, Luchtenborg M, Bruïne de AP, Roemen GM, Lentjes MH, Goldbohm RA, Brandt van den PA, Goeij de AF, Weijenberg MP.
Dietary folate and APC mutations in sporadic colorectal cancer.
J Nutr 2006; 136(12): 3015-3021.
Hellebrekers DM, Castermans K, Vire E, Dings RP, Hoebers NT, Mayo KH, Oude Egbrink MG, Molema G, Fuks F, van Engeland M, Griffioen AW.
Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications.
Cancer Res 2006; 66: 10770-10777
Research group
Dr. Manon van Engeland, molecular biologist, project leader
Prof.dr. Adriaan P. de Bruïne, pathologist
Dr. Nathalie Sieben, pathologist
Dr. Veronique Winnepenninckx, pathologist
Post doctoral fellows
Dr. Debby Hellebrekers, molecular biologist
PhD students
Ingrid Bijsmans
Arjen Cleven
Sarah Derks
Marjolein Lentjes
Veerle Melotte
Marcella Stevens-Baldewijns
Stefan de Vogel
Technicians
Sandra van den Bosch
Kathleen Daenen
Iris Hendriks-Partouns
Peter Moerkerk
Fiona Schot
Angela Spiertz
Kim Wouters
Students
Iris van Vlodrop
Dora Menting