Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association.
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.
Brems
Hilde
H
Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.
Park
Caroline
C
Maertens
Ophélia
O
Pemov
Alexander
A
Messiaen
Ludwine
L
Messia
Ludwine
L
Upadhyaya
Meena
M
Claes
Kathleen
K
Beert
Eline
E
Peeters
Kristel
K
Mautner
Victor
V
Sloan
Jennifer L
JL
Yao
Lawrence
L
Lee
Chyi-Chia Richard
CC
Sciot
Raf
R
De Smet
Luc
L
Legius
Eric
E
Stewart
Douglas R
DR
D000199:Actins / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D002648:Child; D055028:Comparative Genomic Hybridization; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D018628:Gene Dosage; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D005918:Glomus Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D012867:Skin / Q000166:cytology; D014407:Tumor Cells, Cultured; D055815:Young Adult; D018631:ras Proteins / Q000378:metabolism
C541116:ACTA2 protein, human; D000199:Actins; D011944:Receptors, Androgen; D018631:ras Proteins