Publications (145) View all
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Article: Growth behavior of plexiform neurofibromas after surgery.
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ABSTRACT: Purpose:The aim of this study was to analyze growth rate and identify prognostic factors for progression of postoperative plexiform neurofibromas in patients with neurofibromatosis type 1.Methods:We measured postoperative tumor volume change per year on magnetic resonance imaging. Linear regression models were applied to identify risk factors for tumor progression.Results:Fifty-two patients (mean age: 25.4 years (3.2-64.2 years)) with 56 plexiform neurofibromas were analyzed. Initial median tumor volume was 40.3 ml (SD: 1,552 (0-10,800)). Surgical indications included disfigurement (n = 21), pain (n = 20), and functional deficits (n = 16). Sixteen percent of all cases experienced acute surgical complication, and 13% showed late complication. Eight patients (19%; 6 children and 2 adults) with residual tumor had repeat surgery for tumor progression. Median tumor progression was 0.6% change per year (SD ± 27.4; range: -59.2 to 88.1) and 2.9% from baseline (SD ± 163.9; range -1,001.3 to 81.8). Patients aged 21 years and younger had the highest progression rate (P < 0.01). For every year of age, the mean growth rate decreased by -0.463 mean percent (P = 0.03). With age as a continuous variable, age, the site of the tumor, and depth were the only factors associated with tumor progression. Fourteen plexiform neurofibromas (10 nodular and 4 diffuse) in 13 patients (5 children and 8 adults) were completely resected (by visualization) and did not relapse during observation (mean: 2.9 years; range: 1.1-5.8 years).Conclusion:Age, tumor type, location, and depth are helpful to estimate the progression of plexiform neurofibromas after surgery. Patients benefit from elective surgery of small and completely removable plexiform neurofibromas.Genet Med advance online publication 18 April 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.30.Genetics in medicine: official journal of the American College of Medical Genetics 04/2013; · 3.92 Impact Factor -
Article: Merlin isoform 2 in neurofibromatosis type 2-associated polyneuropathy.
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ABSTRACT: The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.Nature Neuroscience 03/2013; · 15.53 Impact Factor -
Article: Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions.
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ABSTRACT: BACKGROUND: Neurofibromatosis type-1 (NF1) is caused by mutations of the NF1 gene at 17q11.2. In 95% of non-founder NF1 patients, NF1 mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the NF1 gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional NF1 mutation. The number of plexiform neurofibromas (PNF) in NF1 patients is however a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene ANRIL at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced ANRIL expression, appears to be associated with higher PNF number. ANRIL directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the CDKN2A/CDKN2B tumour suppressor genes as well as for their epigenetic silencing. METHODS: Here, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional NF1 microdeletions using the exact Cochran-Armitage test for trends and the exact Mann--Whitney--Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The NF1 microdeletions observed in these 29 patients encompassed the NF1 gene as well as its flanking regions, including the SUZ12 gene. RESULTS: In the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280. CONCLUSION: Our findings imply that, at least in patients with NF1 microdeletions, PNF susceptibility is not associated with rs2151280. Although somatic inactivation of the NF1 wild-type allele is considered to be the PNF-initiating event in NF1 patients with intragenic mutations and patients with NF1 microdeletions, both patient groups may differ with regard to tumour progression because of the heterozygous constitutional deletion of SUZ12 present only in patients with NF1 microdeletions.BMC Medical Genetics 10/2012; 13(1):98. · 2.33 Impact Factor -
Article: Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1.
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ABSTRACT: BACKGROUND: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). METHODS: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman's rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann--Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth to age group. RESULTS: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (-13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman's rho=-0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median -3.4%/year [-0.07% to -35.9%/year]). CONCLUSION: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs.Orphanet Journal of Rare Diseases 10/2012; 7(1):75. · 5.83 Impact Factor -
Article: Molecular heterogeneity in malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1.
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ABSTRACT: Neurofibromatosis type-1 (NF1), resulting from NF1 gene loss of function, is characterizedby an increased risk of developing benign and malignant peripheral nerve sheath tumors(MPNSTs). Whereas the cellular heterogeneity of NF1-associated tumors has been wellstudied, the molecular heterogeneity of MPNSTs is still poorly understood. Mutationalheterogeneity within these malignant tumors greatly complicates the study of the underlyingmechanisms of tumorigenesis. We have explored this molecular heterogeneity by performingloss of heterozygosity (LOH) analysis of the NF1, TP53, RB1, PTEN, and CDKN2A genes onsections of 10 MPNSTs derived from 10 unrelated NF1 patients. LOH data for the TP53 genewas found to correlate with the results of p53 immunohistochemical analysis in the sametumor sections. Further, approximately 70% of MPNSTs were found to display intra-tumoralmolecular heterogeneity as evidenced by differences in the level of LOH between differentsections of the same tumor samples. This study constitutes the first systematic analysis ofmolecular heterogeneity within MPNSTs derived from NF1 patients. Appreciation of theexistence of molecular heterogeneity in NF1-associated tumors is important not only foroptimizing somatic mutation detection, but also for understanding the mechanisms of NF1tumorigenesis, a prerequisite for the development of specifically targeted cancer therapeutics.Human genomics 09/2012; 6(1):18.
