Biomedical subjects

Remco van Doorn

Publications and source records attributed to Remco van Doorn.

8 recordsLinked to original sources

PubMed2026

Histopathologic, Genomic, and Clinical Characteristics of Primary Cutaneous Melanocytic Tumors With Concomitant NRAS Q61 and IDH1 R132C Mutations.

Cutaneous melanocytic tumors with concomitant NRAS Q61 and IDH1 R132C mutations have been described as intermediate-grade melanocytomas with characteristic biphasic morphology, but the malignant end of this genotype-defined spectrum remains poorly characterized. We assessed histopathologic, immunohistochemical, molecular, and clinical features of 16 primary cutaneous melanocytic tumors harboring both mutations. Following integrated review, 7 tumors were classified as melanocytoma and 9 as melanoma. Melanocytomas showed reproducible biphasic architecture with congenital nevus-like features, a biphasic HMB-45 pattern, low Ki-67, PRAME negativity, retained p16, and minimal copy number variations (CNVs). Melanomas retained partial morphologic overlap in a subset but were distinguished by higher-grade cytology, immunohistochemical features supportive of malignancy, and progression-associated genomic alterations, including TERT promoter mutation (9/9), 9p21/CDKN2A loss (4/7), and higher CNV burden. NRAS and IDH1 variant allele frequencies were strongly concordant (r = 0.83, P < 0.001), supporting their presence in the same dominant clone. Clinically, two patients presented with stage IIIB disease, but no distant metastasis or melanoma-related death occurred during a median melanoma follow-up of 3.9 years (IQR, 2.5-5.1). In exploratory analyses, moderate-to-severe atypia (RR, 6.2; 95% CI, 1.0-38.8; P = .009), Ki-67 ≥10% (RR, 4.4; 95% CI, 1.1-18.4; P = .003), lymphocytic infiltrate (RR, 2.4; 95% CI, 1.1-5.3; P = .03), absence of the typical biphasic pattern (RR, 2.4; 95% CI, 1.1-5.3; P = .03), and complete p16 loss (RR, 2.4; 95% CI, 1.1-5.3; P = .03) were associated with molecular or clinical progression to melanoma, defined as the presence of at least one of the following: TERT promoter mutation, pathogenic CDKN2A mutation, 9p21/CDKN2A loss, ≥3 genome-wide segmental CNVs, or any metastasis. These findings support the existence of NRAS/IDH1 co-mutated melanoma as the malignant counterpart of NRAS/IDH1-mutated melanocytoma within a single genotype-defined spectrum.

IDH1 mutations↗

PubMed2006

Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities.

CD4+CD56+ hematodermic neoplasm (CD4+CD56+HN) is an aggressive hematopoietic malignancy with distinct clinicopathologic and immunophenotypic features that commonly involve the skin, bone marrow, and blood. Differentiation from cutaneous myelomonocytic leukemia (c-AML) may be exceedingly difficult and requires extensive phenotyping. The molecular mechanisms involved in the development of CD4+CD56+HN are largely unresolved. Moreover, recurrent chromosomal alterations have not yet been precisely defined in CD4+CD56+HN and c-AML. In the present study an integrated genomic analysis using expression profiling and array-based comparative genomic hybridization (CGH) was performed on lesional skin biopsy samples of patients with CD4+CD56+HN and c-AML. Our results demonstrate that CD4+CD56+HN and c-AML show distinct gene-expression profiles and distinct patterns of chromosomal aberrations. CD4+CD56+HN is characterized by recurrent deletion of regions on chromosome 4 (4q34), chromosome 9 (9p13-p11 and 9q12-q34), and chromosome 13 (13q12-q31) that contain several tumor suppressor genes with diminished expression (Rb1, LATS2). Elevated expression of the oncogenes HES6, RUNX2, and FLT3 was found but was not associated with genomic amplification. We noted high expression of various plasmacytoid dendritic-cell (pDC)-related genes, pointing to the cell of origin of this malignancy.

Aged↗

PubMed2005

Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.

PURPOSE: To analyze the occurrence of promoter hypermethylation in primary cutaneous T-cell lymphoma (CTCL) on a genome-wide scale, focusing on epigenetic alterations with pathogenetic significance. MATERIALS AND METHODS: DNA isolated from biopsy specimens of 28 patients with CTCL, including aggressive CTCL entities (transformed mycosis fungoides and CD30-negative large T-cell lymphoma) and an indolent entity (CD30-positive large T-cell lymphoma), were investigated. For genome-wide DNA methylation screening, differential methylation hybridization using CpG island microarrays was applied, which allows simultaneous detection of the methylation status of 8640 CpG islands. Bisulfite sequence analysis was applied for confirmation and detection of hypermethylation of eight selected tumor suppressor genes. RESULTS: The DNA methylation patterns of CTCLs emerging from differential methylation hybridization analysis included 35 CpG islands hypermethylated in at least four of the 28 studied CTCL samples when compared with benign T-cell samples. Hypermethylation of the putative tumor suppressor genes BCL7a (in 48% of CTCL samples), PTPRG (27%), and thrombospondin 4 (52%) was confirmed and demonstrated to be associated with transcriptional downregulation. BCL7a was hypermethylated at a higher frequency in aggressive (64%) than in indolent (14%) CTCL entities. In addition, the promoters of the selected tumor suppressor genes p73 (48%), p16 (33%), CHFR (19%), p15 (10%), and TMS1 (10%) were hypermethylated in CTCL. CONCLUSION: Malignant T cells of patients with CTCL display widespread promoter hypermethylation associated with inactivation of several tumor suppressor genes involved in DNA repair, cell cycle, and apoptosis signaling pathways. In view of this, CTCL may be amenable to treatment with demethylating agents.

Adult↗

PubMed2005

Aberrant DNA methylation in cutaneous malignancies.

In recent years it has become evident that in addition to genetic mutations also epigenetic alterations are causally related to the development and progression of cancer. The epigenetic mechanism most relevant in the pathogenesis of cancer appears to be aberrant methylation of tumor-suppressor gene promoters associated with transcriptional downregulation. Malignancies arising in the skin are the most prevalent in humans. The most common are basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), melanoma, and cutaneous lymphoma. The visibility and accessibility of cutaneous tumors facilitate the scientific study of sequential epigenetic alterations occurring during tumorigenesis and might make treatment of malignant skin lesions using locally applied demethylating agents possible. In this review, we summarize the current knowledge concerning alterations of DNA methylation in BCC, SCC, melanoma, and cutaneous lymphoma. Furthermore, the potential "epigenotoxic" effects of ultraviolet radiation, an environmental carcinogen implicated in the tumorigenesis of most cutaneous malignancies, will be discussed. From the limited number of investigations of promoter hypermethylation in cutaneous malignancies, it is already clear that a great number of potential tumor-suppressor genes are epigenetically silenced in skin cancer, including components of signaling pathways critical in the pathogenesis of these malignancies.

Basal Cell Carcinoma↗

PubMed2004

Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis.

Sézary syndrome (Sz) is a malignancy of CD4+ memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4+ T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis and healthy controls. Using unsupervised hierarchical clustering gene, expression patterns of T cells from patients with Sz were classified separately from those of benign T cells. One hundred twenty-three genes were identified as significantly differentially expressed and had an average fold change exceeding 2. T cells from patients with Sz demonstrated decreased expression of the following hematopoietic malignancy-linked tumor suppressor genes: TGF-beta receptor II, Mxi1, Riz1, CREB-binding protein, BCL11a, STAT4, and Forkhead Box O1A. Moreover, the tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sz. High expression of EphA4 and Twist was also observed in lesional skin biopsy specimens of a subset of patients with cutaneous T cell lymphomas related to Sz, whereas their expression was nearly undetectable in benign T cells or in skin lesions of patients with inflammatory dermatoses. Detection of EphA4 and Twist may be used in the molecular diagnosis of Sz and related cutaneous T-cell lymphomas. Furthermore, the membrane-bound EphA4 receptor may serve as a target for directed therapeutic intervention.

Female↗

PubMed2003

Genetic and clinical mosaicism in a patient with neurofibromatosis type 1.

Patients with typical features of neurofibromatosis type 1 (NF1) limited to a specific body segment are usually referred to as having "segmental NF1", which is generally assumed to be the result of somatic mosaicism for a NF1 mutation. Mosaicism has also been demonstrated at the molecular level in some sporadic cases with phenotypically classic NF1. In the present report, we describe a patient with NF1 disease manifestations throughout the whole body, but leaving a few sharply delineated segments of the skin unaffected, suggestive of revertant mosaicism. A large intragenic deletion was found by mutation analysis using long-range RT-PCR. The intra-exonic breakpoints were characterized in exon 13 and exon 28, resulting in a deletion of 99,571 bp at the genomic level. The presence of two genetically distinct cell populations, confirming mosaicism for this NF1 mutation, was shown by analysis of several tissues. Revertant mosaicism was excluded by demonstrating heterozygosity for markers residing in the deletion region. The findings in this patient demonstrate two things: (1) although the entire body is affected, mosaicism can still be suspected at clinical examination and proven by DNA analysis and skin biopsies; (2) long-range RT-PCR is a feasible method for demonstrating large intragenic deletions in NF1.

Adult↗

PubMed2002

A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma.

Defective apoptosis signaling has been implicated in the pathogenesis of primary cutaneous T-cell lymphomas (CTCLs), a group of malignancies derived from skin-homing T cells. An important mediator of apoptosis in T cells is the Fas receptor. We identified a novel splice variant of the Fas gene that displays retention of intron 5 and encodes a dysfunctional Fas protein in 13 of 22 patients (59%) in both early and advanced CTCL. Impairment of Fas-induced apoptosis resulting from aberrant splicing potentially contributes to the development and progression of CTCL by allowing continued clonal expansion of activated T cells and by reducing susceptibility to antitumor immune responses.

Aged↗

PubMed2002

Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients.

OBJECTIVE: To determine the clinicopathologic features and the disease course of patients with follicular mycosis fungoides (MF). DESIGN: A multicenter, 14-year, retrospective cohort analysis. SETTING: Dutch Cutaneous Lymphoma Group. PATIENTS: Fifty-one patients with the clinicopathologic features of follicular MF with (n = 49) or without (n = 2) associated follicular mucinosis. Follow-up data were compared with those of 158 patients with the classic epidermotropic type of MF, including 122 patients with generalized plaque-stage MF (T2 N0 M0) and 36 patients with tumor-stage MF (T3 N0 M0). OBSERVATIONS: Characteristic clinical features not or rarely observed in classic MF were the preferential localization of the skin lesions in the head and neck region (45 of 51 patients), the presence of follicular papules, alopecia, acneiform lesions, mucinorrhoea, and often severe pruritus. Characteristic histologic findings were the presence of perifollicular neoplastic infiltrates with a variable degree of folliculotropism, but generally no epidermotropism, follicular mucinosis (49 of 51 cases), and often a considerable admixture of eosinophils and plasma cells. Response on initial treatment, risk of disease progression (development of extracutaneous disease and/or death from lymphoma), and disease-specific and overall survival of patients with follicular MF were worse than in classic MF patients. The actuarial disease-specific survival was 68% at 5 years and 26% at 10 years. CONCLUSIONS: Follicular MF shows distinctive clinicopathologic features, is more refractory to treatment, and has a worse prognosis than the classic type of MF; it should be considered a distinct type of cutaneous T-cell lymphoma. Based on these results and those of other studies, we suggest the term follicular MF for cases with or without associated follicular mucinosis.

Adolescent↗