Remco van Doorn

University of Leeds, Leeds, England, United Kingdom

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Publications (41)267.06 Total impact

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    ABSTRACT: The activation of oncogenes in primary cells blocks proliferation by inducing oncogene-induced senescence (OIS), a highly potent in vivo tumor-suppressing program. A prime example is mutant BRAF, which drives OIS in melanocytic nevi. Progression to melanoma occurs only in the context of additional alteration(s) like the suppression of PTEN, which abrogates OIS. Here, we performed a near-genomewide short hairpin (sh)RNA screen for novel OIS regulators and identified by next generation sequencing and functional validation seven genes. While all but one were upregulated in OIS, their depletion abrogated BRAF(V) (600E) -induced arrest. With genome-wide DNA methylation analysis we found one of these genes, RASEF, to be hypermethylated in primary cutaneous melanomas compared to nevi. Bypass of OIS by depletion of RASEF was associated with suppression of several senescence biomarkers including senescence-associated (SA)-β-galactosidase activity, interleukins and tumor suppressor p15(INK) (4B) . Restoration of RASEF expression inhibited proliferation. These results illustrate the power of shRNA OIS bypass screens and identify a potential novel melanoma suppressor gene. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 04/2014; · 5.84 Impact Factor
  • Gudula Kirtschig, Tim van Meurs, Remco van Doorn
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    ABSTRACT: Topical imiquimod cream is increasingly applied in the treatment of lentigo maligna (LM), in particular for large lesions where surgery may lead to disfiguring scars. Published studies suggest that more frequent and prolonged treatment with topical imiquimod is associated with higher efficacy. In this study we prospectively treated 27 patients suffering from LM of the face with imiquimod 5% cream using an intensive treatment regimen consisting of daily applications for 12 weeks inducing at least 10 weeks skin inflammation. Twenty-four patients completed the treatment as recommended, 23 were available for follow-up (mean 39 months). Clinical and histopathological clearance was observed in 20 patients after on average 14 weeks of treatment. Notably, histopathological examination of a skin biopsy showed clearance of the LM in all 24 patients, including those who still showed some hyperpigmentation at 4 weeks off treatment. A clinical recurrence occurred in only 1 of the 24 treated patients. These findings suggest that the efficacy of imiquimod can be improved by implementing a more intensive treatment regimen. Randomized controlled trials are needed to confirm our results and establish the role of topical imiquimod in the treatment of LM.
    Acta Dermato-Venereologica 04/2014;
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    ABSTRACT: We report the association of an inherited variant located upstream of the poly (adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role for the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (Hazard ratio (HR)=1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, 11 cohorts) and MSS (HR=1.20 per allele, 95%CI 1.01-1.39, p=0.03, 8 cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; · 6.20 Impact Factor
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    ABSTRACT: An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced OS in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% CI 0.93,1.64. In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88,1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93,1.29). There was evidence of increased melanoma specific deaths in the 7 cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 11/2013; · 5.84 Impact Factor
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    ABSTRACT: It is generally thought that class III β-tubulin expression is limited to cells of the neural lineage and is therefore often used to identify neurons amongst other cell types, both in vivo and in vitro. Melanocytes are derived from the neural crest and share both morphological features and functional characteristics with peripheral neurons. Here, we show that these similarities extend to class III β-tubulin (TUBB3) expression, and that human melanocytes express this protein both in vivo and in vitro. In addition, we studied the expression of class III β-tubulin in two murine melanogenic cell lines and show that expression of this protein starts as melanoblasts mature into melanocytes. Melanin bleaching experiments revealed close proximity between melanin and TUBB3 proteins. In vitro stimulation of primary human melanocytes by α-MSH indicated separate regulatory mechanisms for melanogenesis and to TUBB3 expression. Together, these observations imply that human melanocytes express TUBB3 and that this protein should be recognized as a wider marker for multiple neural crest-derived cells.
    Differentiation 06/2013; 85(4-5):173-181. · 2.86 Impact Factor
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    Journal of Investigative Dermatology 06/2013; · 6.19 Impact Factor
  • I Koelemij, E T Massolt, R van Doorn
    Clinical and Experimental Dermatology 05/2013; · 1.33 Impact Factor
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    ABSTRACT: The involvement of epigenetic alterations in the pathogenesis of melanoma is increasingly recognized. Here, we performed genome-wide DNA methylation analysis of primary cutaneous melanoma and benign melanocytic nevus interrogating 14 495 genes using BeadChip technology. This genome-wide view of promoter methylation in primary cutaneous melanoma revealed an array of recurrent DNA methylation alterations with potential diagnostic applications. Among 106 frequently hypermethylated genes, there were many novel methylation targets and tumor suppressor genes. Highly recurrent methylation of the HOXA9, MAPK13, CDH11, PLEKHG6, PPP1R3C, and CLDN11 genes was established. Promoter methylation of MAPK13, encoding p38δ, was present in 67% of primary and 85% of metastatic melanomas. Restoration of MAPK13 expression in melanoma cells exhibiting epigenetic silencing of this gene reduced proliferation, indicative of tumor suppressive functions. This study demonstrates that DNA methylation alterations are widespread in melanoma and suggests that epigenetic silencing of MAPK13 contributes to melanoma progression.
    Pigment Cell & Melanoma Research 03/2013; · 5.84 Impact Factor
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    ABSTRACT: Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFβ) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1's ability to potently downregulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de-differentiates cells into a pro-invasive cell state concomitant with TGFβ activation. Our analysis of publicly available data sets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFβ therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention.Oncogene advance online publication, 25 February 2013; doi:10.1038/onc.2013.30.
    Oncogene 02/2013; · 7.36 Impact Factor
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    ABSTRACT: Paraneoplastic dermatoses may be the first manifestation of a malignancy. Rapid recognition is therefore important. A 72-year-old woman who had been treated in the past for metastasised neuroendocrine carcinoma and had undergone curative treatment for stage-1c endometrial carcinoma developed three paraneoplastic dermatoses over a 2-year period: acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa. Half a year later, cutaneous metastases derived from the endometrial carcinoma treated 12 years prior were discovered. The development of three paraneoplastic dermatoses in a short period of time is rare. Acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa can develop in association with both neuroendocrine and endometrial carcinoma. The sudden development of paraneoplastic dermatoses is frequently a forewarning of progression of the malignancy.
    Nederlands tijdschrift voor geneeskunde 01/2013; 157(38):A6560.
  • K Szuhai, R van Doorn, C P Tensen, Van Kester
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    ABSTRACT: This chapter describes a study in which the pattern of numerical chromosomal alterations in cutaneous anaplastic large cell lymphoma (C-ALCL) tumor samples was defined using array-based comparative genomic hybridization (CGH). First, the array-based CGH technique applied is outlined in detail. Next, its application in the analysis of C-ALCL tumor specimens is described. This approach resulted in the identification of highly recurrent chromosomal alterations in C-ALCL that include gain of 7q31 and loss on 6q16-6q21 and 13q34, each affecting 45% of the patients. The pattern characteristic of C-ALCL differs markedly from chromosomal alterations observed in other CTCL such as mycosis fungoides and Sézary syndrome and yielded several candidate genes with potential relevance in the pathogenesis of C-ALCL.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 973:197-212.
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    Nelleke A Gruis, Remco van Doorn
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    ABSTRACT: Variants in the MC1R gene influence skin pigmentation and thereby modulate risk of melanoma and basal and squamous cell carcinoma. In this issue, Kinsler et al. report an association between the MC1R genotype and the development of congenital melanocytic nevi. Further, higher birth weight was observed in carriers of MC1R variants, suggesting a role for the melanocortin network in fetal growth.
    Journal of Investigative Dermatology 08/2012; 132(8):1953-5. · 6.19 Impact Factor
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    ABSTRACT: Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL). To identify a molecular signature characteristic of MF tumor stage, we used a bioinformatic approach involving meta-analysis of publicly available gene expression data sets combined with previously generated gene expression data. Results for a selection of genes were further refined and validated by quantitative PCR and inclusion of additional controls. With this approach, we identified a profile specific for MF tumor stage, consisting of 989 aberrantly expressed genes, the majority of which (718 genes) are statistically significantly more expressed in MF compared with normal skin, inflamed skin, and normal T cells. As expected, the signature contains genes reflecting the highly proliferative characteristic of this T-cell malignancy, including altered expression of cell cycle and kinetochore regulators. We uncovered details of the immunophenotype, suggesting that MF originates from IL-32-producing cells and identified previously unreported therapeutic targets and/or diagnostic markers, for example, GTSF1 and TRIP13. Loss of expression of the NF-κB inhibitor, NFKBIZ, may partly explain the enhanced activity of NF-κB, which is a hallmark of MF and other CTCLs.
    Journal of Investigative Dermatology 04/2012; 132(8):2050-9. · 6.19 Impact Factor
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    ABSTRACT: Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46-0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65-0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67-1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients.
    Pigment Cell & Melanoma Research 02/2012; 25(3):384-94. · 5.84 Impact Factor
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    ABSTRACT: Cutaneous melanoma, a type of skin tumor originating from melanocytes, often develops from premalignant naevoid lesions via a gradual transformation process driven by an accumulation of (epi)genetic lesions. These dysplastic naevi display altered morphology and often proliferation of melanocytes. Additionally, melanocytes in dysplastic naevi show structural mitochondrial and melanosomal alterations and have elevated reactive oxygen species (ROS) levels. For this study we performed genome-wide expression and proteomic analysis of melanocytes from dysplastic naevus (DNMC) and adjacent normal skin (MC) from 18 patients. Whole genome expression profiles of the DNMC and MC of each individual patient subjected to GO-based comparative statistical analysis yielded significantly differentially expressed GO classes including "organellar ribosome," "mitochondrial ribosome," "hydrogen ion transporter activity," and "prefoldin complex." Validation of 5 genes from these top GO classes revealed a heterogeneous differential expression pattern. Proteomic analysis demonstrated differentially expressed proteins in DNMC that are involved in cellular metabolism, detoxification, and cytoskeletal organization processes, such as GTP-binding Rho-like protein CDC42, glutathione-S-transferase omega-1 and prolyl 4-hydroxylase. Collectively these results point to deregulation of cellular processes, such as metabolism and protein synthesis, consistent with the observed elevated oxidative stress levels in DNMC potentially resulting in oxidative DNA damage in these cells.
    Journal of skin cancer. 01/2012; 2012:981308.
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    ABSTRACT: Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.
    Cancer cell 07/2011; 20(1):92-103. · 25.29 Impact Factor
  • Roel E Genders, Maarten H Vermeer, Remco van Doorn
    British Journal of Haematology 04/2011; 154(2):159. · 4.94 Impact Factor
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    ABSTRACT: Oncogene-induced cellular senescence (OIS) is an increasingly recognized tumour suppressor mechanism that confines the outgrowth of neoplastic cells in vivo. It relies on a complex signalling network, but only few components have been identified so far. Gene-expression profiling revealed a >100-fold increase in the levels of the transcription factor and putative tumour suppressor gene TGFβ-stimulated clone 22 (TSC22D1) in BRAF(E600)-induced senescence, in both human fibroblasts and melanocytes. Only the short TSC22D1 transcript was upregulated, whereas the abundance of the large protein variant was suppressed by proteasomal degradation. The TSC22D1 protein variants, in complex with their dimerization partner TSC22 homologue gene 1 (THG1), exerted opposing functions, as selective depletion of the short form, or conversely, overexpression of the large variant, resulted in abrogation of OIS. This was accompanied by the suppression of several inflammatory factors and p15(INK4B), with TSC22D1 acting as a critical effector of C/EBPβ. Our results demonstrate that the differential regulation of antagonistic TSC22D1 variants is required for the establishment of OIS and suggest distinct contributions of TSC22 family members to the progression of BRAF(E600)-driven neoplasia.
    The EMBO Journal 03/2011; 30(9):1753-65. · 9.82 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are small RNA species that regulate gene expression post-transcriptionally and are aberrantly expressed in many malignancies including lymphoma. However, the role of miRNAs in the pathogenesis of T-cell lymphoid malignancies is poorly understood. Previously we examined the miRNA profile of Sézary syndrome (Sz), a leukemia of skin-homing memory T cells. In this study we determined the complete miRNome of mycosis fungoides (MF), the most common type of cutaneous T cell lymphoma. The miRNA profile of skin biopsies from 19 patients with tumor stage MF and 12 patients with benign inflammatory dermatoses (eczema and lichen planus) were compared by microarray analysis. We identified 49 miRNAs that are differentially expressed in tumor stage MF compared to benign inflammatory dermatoses using ANOVA analysis (P < 0.05, Benjamini-Hochberg corrected). The majority of the differentially expressed miRNAs (30/49) were up-regulated in tumor stage MF. The most significant differentially expressed were miR-155 and miR-92a (both up-regulated in tumor stage MF), while miR-93 showed the highest up-regulation in tumor stage MF with a fold difference of 5.8. Differential expression of a selection of these miRNAs was validated by miRNA-Q-PCR on additional test groups (tumors and controls). None of the miRNAs up-regulated in tumor stage MF was previously shown to be up-regulated in Sz, and only 2 of the 19 miRNAs down-regulated in tumor stage MF were also down-regulated in Sz. Taken together this report is the first describing the miRNA signature of tumor stage MF.
    Molecular oncology 02/2011; 5(3):273-80. · 6.70 Impact Factor

Publication Stats

1k Citations
346 Downloads
2k Views
267.06 Total Impact Points

Institutions

  • 2012–2013
    • University of Leeds
      • • Section of Epidemiology and Biostatistics
      • • Leeds Institute of Molecular Medicine (LIMM)
      Leeds, England, United Kingdom
  • 2002–2012
    • Leiden University Medical Centre
      • Department of Dermatology
      Leiden, South Holland, Netherlands
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2008–2011
    • Netherlands Cancer Institute
      • Division of Molecular Genetics
      Amsterdam, North Holland, Netherlands
  • 2000
    • University of Amsterdam
      • Department of Dermatology
      Amsterdam, North Holland, Netherlands