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

American Association for Cancer Research (AACR) - Tập 69 Số 18 - Trang 7393-7401 - 2009
Hilde Brems1, Caroline Park2, Ophélia Maertens3,4, Alexander Pemov5, Ludwine Messiaen6, Meena Upadhyaya7, Kathleen Claes3, Eline Beert1, Kristel Peeters1, Victor Mautner8, Jennifer L. Sloan9, Lawrence Yao10, Chyi‐Chia Richard Lee11, Raf Sciot12, Luc De Smet13, Eric Legius1, Douglas R. Stewart5
11Human Genetics and Departments of
23Albert Einstein College of Medicine, Bronx, New York;
311Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium;
44Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
55Genetic Disease Research Branch and
69Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama;
710Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom;
812Laboratory for Tumor Biology and Developmental Disorders, Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany; and
96Genetic and Molecular Biology Branch, National Human Genome Research Institute, NIH;
107Department of Radiology, Clinical Center and
118Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland;
122Pathology, Catholic University Leuven, Leuven, Belgium;
1313Department of Orthopaedic Surgery, University Hospital Pellenberg, Lubbeek, Belgium

Tóm tắt

Abstract 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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American Association for Cancer Research (AACR)

Tập 69 Số 18

7393-7401

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