Dermatology 1

Dermato-oncology

Principal Investigators

Dr J.N. Bouwes Bavinck, Dr R. van Doorn, Dr A. El Ghalbzouri, Dr F.R. de Gruijl, Dr N.A. Gruis, Dr S. Pavel, Dr C.P. Tensen, Dr M.H. Vermeer, Prof.Dr R. Willemze

Aim and focus

The skin cancer research program includes three main lines of research: 1. (familial) melanoma; 2. skin carcinoma, particularly in organ-transplant patients, and 3. cutaneous lymphoma. These have in common a combination of basic, translational and clinical research, coordination by a dermatologist and basic scientist and patient groups for which the Dept. of Dermatology serves as a tertiary referral center. The central theme within all three lines of research is molecular pathogenesis including characterization of successive stages of tumor progression. Methods employed include microarray based technology, proteomics and epidemiological studies to identify relevant risk factors as well as new diagnostic and prognostic markers. Cell cultures among which the human skin equivalent and transgenic mouse models are used in experiments on pathogenesis, e.g. by UV, and to identify and validate new targets for therapeutic or preventive intervention.

Position in international context

All three lines of research play an important role in international skin cancer networks:
Our melanoma group is one of the key players in the International Melanoma Genetics Consortium (GenoMEL), which was founded in 1997. The group participates in many collaborative projects on penetrance, susceptibility and modifying genes and gene-environment interactions, and is now formalized in an EU network of excellence.
The longstanding research on skin carcinogenic risk factors, most specifically HPV in renal transplant patients has resulted in many EU funded collaborative studies. The department's expertise on UV carcinogenesis is sought in international commissions on health and environmental issues (e.g. the UNEP panel on the effects of a depletion of stratospheric ozone).
The cutaneous lymphoma group has a lead position within international efforts (EORTC; ISCL) to formulate new classifications for cutaneous lymphomas, and to develop guidelines for diagnosis and treatment.
The department has a long-standing experience in using cultured reconstructed human skin equivalents in different research areas. This model is the best-characterized skin model available to date, and recapitulates most of the in vivo characteristics.

Content / highlights / achievements

• Identification of genetic (p16-Leiden mutation; MC1R) and environmental risk factors (ultraviolet radiation and infection with human papillomaviruses) for familial melanoma and skin cancer.
• Optimization of cultured human skin equivalents allowing studies on early oncogenic events.
• Validation of the Leiden human skin model according the ECVAM guidelines for skin corrosivity and irritation.
• Clinicopathologic studies, expression profiling and DNA methylation studies identified new diagnostic and prognostic markers and potential novel therapeutic targets for the most common types of cutaneous lymphoma, and contributed significantly to the WHO-EORTC and WHO 2008 classification for (cutaneous) lymphomas.
• VIDI-grant (Dr. M.H. Vermeer); LUMC Marie Parijs Prize (Dr. N.A. Gruis (2006) and Dr. M.H. Vermeer (2007)). The public ‘Alternatives to Animal Use’ Award for in vitro skin model (dr. A.El Ghalbzouri; 2008). The program aiming at the development of an in vitro three-dimensional model of primary human cutaneous squamous cell carcinoma was selected as a “Pearl project” by ZonMw (2009).

Future themes

In the next five years molecular characterization of the subsequent stages of tumor progression, identification of (genetic) risk factors, genotype - phenotype correlations will remain central themes within all three lines of research. In addition, the role of epigenetic factors as well as protein-protein and protein-DNA interactions and functional analysis of candidate genes will be studied. In 2009 we will start a multicenter EORTC supervised trial on validation of diagnostic and prognostic biomarkers for erythrodermic cutaneous T-cell lymphoma. Functional studies using in vitro (skin)models and murine studies are currently further developed to translate observations from molecular studies to biological insight. In view of its unique potential for skin cancer research the department will invest in further refinement and exploitation of the cultured human skin equivalent.

Cohesion within LUMC

Within the three lines of research there is extensive collaboration with more than 10 departments within the LUMC as well as departments from the University of Leiden (Faculty of Science).

Key publications

Senff NJ, Hoefnagel JJ, Jansen PM, Vermeer MH, van Baarlen J, Blokx WA, Canninga-van Dijk MR, Geerts ML, Hebeda KM, Kluin PM, Lam KH, Meijer CJ, Willemze R. Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers. J Clin Oncol. 2007 Apr 20;25(12):1581-7.
IF 13,6

van Doorn R, van Kester MS, Dijkman R, Vermeer MH, Mulder AA, Szuhai K, Knijnenburg J, Boer JM, Willemze R, Tensen CP. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome Blood. 2009 Jan 1;113(1):127-36.
IF 9.8

Dijkman R, van Doorn R, Szuhai K, Willemze R, Vermeer MH, Tensen CP. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood. 2007 Feb 15;109(4):1720-7.
IF 9.8

Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, Dummer R, Duvic M, Hoppe RT, Pimpinelli N, Rosen ST, Vermeer MH, Whittaker S, Willemze R; European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood. 2008 Sep 1;112(5):1600-9.
IF 9.8

Nijhof JG, Braun KM, Giangreco A, van Pelt C, Kawamoto H, Boyd RL, Willemze R, Mullenders LH, Watt FM, de Gruijl FR, van Ewijk W The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development. 2006 Aug;133(15):3027-37
IF 9.2

Bouwes Bavinck JN, Euvrard S, Naldi L, Nindl I, Proby CM, Neale R, Abeni D, Tessari GP, Feltkamp MC, Claudy A, Stockfleth E, Harwood CA; EPI-HPV-UV-CA group. Keratotic skin lesions and other risk factors are associated with skin cancer in organ-transplant recipients: a case-control study in The Netherlands, United Kingdom, Germany, France, and Italy. J Invest Dermatol. 2007 Jul;127(7):1647-56.
IF 5.2

El Ghalbzouri A, Commandeur S, Rietveld MH, Mulder AA, Willemze R. Replacement of animal-derived collagen matrix by human fibroblast-derived dermal matrix for human skin equivalent products. Biomaterials. 2008 Oct 4. [Epub ahead of print] PMID: 18838164
IF 6.3

de Snoo FA, Bishop DT, Bergman W, van Leeuwen I, van der Drift C, van Nieuwpoort FA, Out-Luiting CJ, Vasen HF, ter Huurne JA, Frants RR, Willemze R, Breuning MH, Gruis NA. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008;14:7151-7.
IF 6.4

Brown KM, Macgregor S, Montgomery GW, Craig DW, Zhao ZZ, Iyadurai K, Henders AK, Homer N, Campbell MJ, Stark M, Thomas S, Schmid H, Holland EA, Gillanders EM, Duffy DL, Maskiell JA, Jetann J, Ferguson M, Stephan DA, Cust AE, Whiteman D, Green A, Olsson H, Puig S, Ghiorzo P, Hansson J, Demenais F, Goldstein AM, Gruis  NA, Elder DE, Bishop JN, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Martin NG, Trent JM, Mann GJ, Hayward NK. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet. 2008;40:838-40.
IF 30.2

Bishop-DT, Demenais-F, Iles M.M, Harland M, Taylor J.C, Corda E, Randerson-Moor J, Aitken JF, Avril M-F, Azizi E, Bakker B, Bianchi-Scarra G, Bressac-de Paillerets B, Calista D, Cannon-Albright L, Chin-a-Woeng T, Debniak T, Galore-Haskel G, Ghiorzo P, Gut I, Hansson J, Hocevar M, Hoiom V, John L Hopper JL, Ingvar C, Kanetsky PA, Kefford RF, Landi MT, Lang J, Lubinski J, Mackie R, Malvehy J, Mann GJ, Martin NG, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Puig S, Weiss M, van Workum W, Zelenika D, Brown KM, Goldstein AM, Gillanders EM, Boland A, Galan P, Elder DE, Gruis NA, Hayward NK, Lathrop GM, Barrett JH, Newton Bishop JA. Genome-wide association study identifies three loci associated with melanoma risk. Nature Genet. Epub ahead 2009
IF 30.2