Remco van Doorn

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (47)304.16 Total impact

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    ABSTRACT: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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    ABSTRACT: Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
    JNCI Journal of the National Cancer Institute 10/2014; 106(10). DOI:10.1093/jnci/dju267 · 15.16 Impact Factor
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    ABSTRACT: At least 17 genomic regions are established as harbouring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1000 Genomes reference panel, we have fine-mapped these regions in over 5000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7000 ethnically matched controls. A penalised regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps towards accounting for some of the "missing heritability". © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2014; 136(6). DOI:10.1002/ijc.29099 · 5.01 Impact Factor
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    ABSTRACT: Dysplastic naevi are melanocytic lesions that represent an intermediate stage between common naevus and melanoma. Histopathological distinction of dysplastic naevus from melanoma can be challenging and there is a requirement for molecular diagnostic markers. In this study we examined promoter CpG island methylation of a selected panel of genes, identified in a genome-wide methylation screen, across a spectrum of 405 melanocytic neoplasms. Promoter methylation analysis in common naevi, dysplastic naevi, primary melanomas and metastatic melanomas demonstrated progressive epigenetic deregulation. Dysplastic naevi were affected by promoter methylation of genes that are frequently methylated in melanoma but not in common naevi. We assessed the diagnostic value of the methylation status of five genes in distinguishing primary melanoma from dysplastic naevus. In particular CLDN11 promoter methylation was specific for melanoma as it occurred in 50% of primary melanomas but in only 3% of dysplastic naevi. A diagnostic algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13 and GNMT genes was validated in an independent sample set and helped distinguish melanoma from dysplastic naevus (AUC 0.81). Melanoma-specific methylation of these genes supports the utility as epigenetic biomarkers and could point to their significance in melanoma development.Journal of Investigative Dermatology accepted article preview online, 07 July 2014; doi:10.1038/jid.2014.270.
    Journal of Investigative Dermatology 07/2014; 134(12). DOI:10.1038/jid.2014.270 · 6.37 Impact Factor
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    ABSTRACT: A critical first step in the metastatic progression of cutaneous melanoma, invasive growth into the dermal compartment, would ideally be studied in the proper three-dimensional tissue microenvironment. In this study, we compared the growth and behavior of four melanoma cell lines originating from primary and metastatic human cutaneous melanomas (AN, RU, M14, and WK) in in-vitro human skin equivalents (HSEs) generated with four different dermal matrices: human fibroblast-seeded rat tail collagen, human fibroblast-derived matrix (FDM), noncellular human de-epidermized dermis (DED), and a novel fully cellular human DED with an intact pre-existent basement membrane. Melanoma cells showed proliferation in all HSEs, indicating that the microenvironment formed in all HSEs studied here allows the growth of melanoma cells in concert with epidermal keratinocytes for multiple weeks in vitro. Melanoma cells did not affect epidermal proliferation and terminal differentiation. Growth of melanoma cells in the dermal compartment, as a measure of invasive potential, differs markedly between the four types of in-vitro human melanoma models. Notably, the growth of melanoma cells in the dermal matrix was observed in all HSEs cultured with cell lines originating from metastatic melanoma, except for cDED-based HSEs, and the growth of melanoma cells of nonmetastatic origin was observed in the dermal compartment of FDM-based HSEs. Our results show that the type of dermal equivalent and the presence of an intact basement membrane should be taken into consideration when studying melanoma invasion using in-vitro HSEs.
    Melanoma Research 06/2014; 24(4). DOI:10.1097/CMR.0000000000000079 · 2.10 Impact Factor
  • R van Doorn
    British Journal of Dermatology 06/2014; 170(6):1216. DOI:10.1111/bjd.12870 · 3.76 Impact Factor
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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; 27(4). DOI:10.1111/pcmr.12248 · 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; 95(1). DOI:10.2340/00015555-1861
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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; DOI:10.1002/ijc.28796 · 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; DOI:10.1111/pcmr.12193 · 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. DOI:10.1016/j.diff.2013.05.003 · 2.84 Impact Factor
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    Journal of Investigative Dermatology 06/2013; 134(1). DOI:10.1038/jid.2013.270 · 6.19 Impact Factor
  • I Koelemij, E T Massolt, R van Doorn
    Clinical and Experimental Dermatology 05/2013; 38(8). DOI:10.1111/ced.12133 · 1.23 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; 26(4). DOI:10.1111/pcmr.12096 · 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; DOI:10.1038/onc.2013.30 · 8.56 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. DOI:10.1007/978-1-62703-281-0_13 · 1.29 Impact Factor
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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. DOI:10.1038/jid.2012.216 · 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. DOI:10.1038/jid.2012.117 · 6.19 Impact Factor

Publication Stats

2k Citations
304.16 Total Impact Points

Institutions

  • 2005–2014
    • Leiden University Medical Centre
      • Department of Dermatology
      Leyden, South Holland, Netherlands
  • 2004–2014
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2013
    • University of Leeds
      • Section of Epidemiology and Biostatistics
      Leeds, England, United Kingdom
  • 2011
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2008–2011
    • Netherlands Cancer Institute
      • Division of Molecular Genetics
      Amsterdamo, North Holland, Netherlands
  • 2002
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands