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Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association

Departments of ¹ Human Genetics and ² Pathology, Catholic University Leuven, Leuven, Belgium; ³ Albert Einstein College of Medicine, Bronx, New York; ⁴ Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ⁵ Genetic Disease Research Branch and ⁶ Genetic and Molecular Biology Branch, National Human Genome Research Institute, NIH; ⁷ Department of Radiology, Clinical Center and ⁸ Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland; ⁹ Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama; ¹⁰ Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom; ¹¹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; ¹² Laboratory for Tumor Biology and Developmental Disorders, Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany; and ¹³ Department of Orthopaedic Surgery, University Hospital Pellenberg, Lubbeek, Belgium

Requests for reprints: Douglas R. Stewart, National Human Genome Research Institute, 49 Convent Drive, Building 49, Room 4A62, Bethesda, MD 20892. Phone: 301-451-7716; Fax: 301-402-2170; E-mail: drstewart{at}mail.nih.gov.

Key Words: Neurofibromatosis type 1 • Glomus tumor • Comparative genomic hybridization • RAS-MAPK hyperactivation • Biallelic inactivation

Neurofibromatosis type 1 (NF1) is a common disorder that arises secondary to mutations in the tumor suppressor gene NF1. Glomus tumors are small, benign but painful tumors that originate from the glomus body, a thermoregulatory shunt concentrated in the fingers and toes. We report 11 individuals with NF1 who harbored 20 glomus tumors of the fingers and 1 in the toe; 5 individuals had multiple glomus tumors. We hypothesized that biallelic inactivation of NF1 underlies the pathogenesis of these tumors. In 12 NF1-associated glomus tumors, we used cell culture and laser capture microdissection to isolate DNA. We also analyzed two sporadic (not NF1-associated) glomus tumors. Genetic analysis showed germ line and somatic NF1 mutations in seven tumors. RAS mitogen-activated protein kinase hyperactivation was observed in cultured NF1^–/– glomus cells, reflecting a lack of inhibition of the pathway by functional neurofibromin, the protein product of NF1. No abnormalities in NF1 or RAS mitogen-activated protein kinase activation were found in sporadic glomus tumors. By comparative genomic hybridization, we observed amplification of the 3'-end of CRTAC1 and a deletion of the 5'-end of WASF1 in two NF1-associated glomus tumors. For the first time, we show that loss of neurofibromin function is crucial in the pathogenesis of glomus tumors in NF1. Glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1. [Cancer Res 2009;69(18):7393–401]

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				Correction: Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association Cancer Res., October 15, 2009; 69(20): 8216 - 8216. [Full Text] [PDF]