Molecular Analysis of Extra-Axial Hemangioblastoma. A Study of 6 Cases.
Lucia A Muscarella, Janez Lamovec, Paola Parrella, Nina Zidar, Leonardo D'Agruma, Michele Bisceglia, Vito Guarnieri, Michelina Coco, Julie C Fanburg-Smith, Leopoldo Zelante, Michal Michal. Hospital, San Giovanni Rotondo, Foggia, Italy; Institute of Oncology, Ljubljana, Slovenia; Medical Faculty, University of Ljubliana, Slovenia; Nova Fairfax Hospital, Falls Church, VA; IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia, Italy; Charles University Medical Faculty, Plzen, Czech Republic
Background: Extraneuraxial hemangioblastoma (e-HGB) may occur in various body organs either in the context of von Hippel-Lindau syndrome (VHL) or sporadically. Patients with VHL exhibit mutations of VHL gene. VHL gene is involved also in sporadic HGB. Only 2 cases of e-HGB have been molecularly analyzed so far, without documenting alterations in VHL gene, thus suggesting in one previous study that VHL gene may not be the causative factor of e-HGB.
Design: We report on 6 e-HGB, 4 in intraspinal/paraspinal locations and 2 in peripheral soft tissues, in 6 patients (5 females and 1 male, aged 40 to 74 years). 1 tumor was VHL-associated, 5 were sporadic. Normal and tumoral tissue samples were available from all cases. Characterization of the VHL gene was performed by Mutation, Fluorescent Loss of Heterozygosity (LOH) and Methylation Analysis in all cases. Mutation analysis searched for point mutations in the entire coding sequence and promoter region of the VHL gene, including the exon-intron boundaries. LOH analysis was performed using three microsatellite markers flanking the VHL gene: D3S1335, D3S1038, D3S1317. The methylation status in the promoter region of the VHL gene was determined by Methylation Specific PCR.
Results: Mutation analysis documented in the HGB tumor tissue of the VHL case (case 1) two nucleotide substitutions, the germline c.452T>A substitution in exon 2, creating the aminoacid change I151N, and the somatic c.450G>A substitution in exon 3, resulting in the aminoacid change R167Q. Most notably, a new somatic nucleotide deletion in exon 3 (c.598delA) was found in case 5, causing a frameshift with a premature predicting stop codon at position 201. Microsatellite analysis showed LOH in case 5 (second hit), and in case 4 and case 6 as single hit. Methylation analysis did not disclose promoter methylation in any tumor. No VHL gene alteration was demonstrated in both case 2 and case 3 by any means.
Conclusions: This is the first report of VHL gene alterations identified in e-HGB, confirming that the VHL gene is involved also in e-HGB.
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 6, Monday Afternoon