Diagnostic value of investigating GNAS mutations in fibro-osseous lesions: a retrospective study of 91 cases of fibrous dysplasia and 40 other fibro-osseous lesions

Abstract

nucleotide-binding protein/a-subunit) mutations that induce the activation of G-protein a-subunit participate in the pathogenesis of fibrous dysplasia. The aim of this study was to evaluate the sensitivity and specificity of GNAS mutations in fibrous dysplasia and other fibro-osseous lesions, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. We studied 91 cases of fibrous dysplasia. The quality and/or quantity of genomic DNA were suitable for molecular analysis for 51 cases of fibrous dysplasia. GNAS mutations were investigated by three techniques: high-resolution melting (exon 8), allele-specific PCR (exons 8 and 9) and/or direct DNA sequencing (exons 8 and 9). Fibrous dysplasia samples were classified blind to the GNAS mutation status into six histological subtypes as conventional, fibro-involutive, osteosclerosing, cementifying, osteocartilaginous and with prominent aneurysmal cystic changes. We also studied 14 cases of lowgrade osteosarcoma, 21 cases of ossifying fibroma, 3 cases of osteofibrous dysplasia, 1 case of osseous dysplasia of the jawbone and 1 post-traumatic lesion of the ribs. Twenty-three cases of fibrous dysplasia (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histological subtypes (47%, P ¼ 0.96), regardless of sex (P ¼ 0.44), age (P ¼ 0.90) and location (P ¼ 1). GNAS mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was thus specific to fibrous dysplasia in the context of fibro-osseous lesions. The particular mosaicism of mutant and non-mutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. Investigating this mutation may constitute a valuable complementary diagnostic tool, despite its low sensitivity, particularly in unconventional morphologically different subtypes of fibrous dysplasia. Modern Pathology (2013) 26, 911-921;

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions

“…Investigating GNAS mutations in these lesions is appropriate to rule out fibrous dysplasia. However, routine GNAS genotyping has proven to be difficult on formalin-fixed, decalcified, and paraffin-embedded bone tissues, 15 and no immunohistochemical marker for GNAS mutation is currently available. 24 Although rare in jawbone locations, 25-27 diagnosis of low-grade osteosarcoma should be considered in the context of fibro-osseous lesions due to its specific management.…”

“…Histologically, 11 patients had conventional fibrous dysplasia and 6 had unconventional fibrous dysplasia: 4 osteosclerosing, 1 fibro-involutive, and 1 with prominent aneurysmal cystic changes, as previously described. 15 Psammomatoid extra-craniofacial fibrous dysplasia. We also studied two unusual cases of extra-craniofacial psammomatoid fibrous dysplasia because of their morphological similarity to ossifying fibroma.…”

“…12,13 These mutations have not been described in other fibro-osseous lesions and roughly 50% of fibrous dysplasia lesions are found to be mutated. 14,15 Recent studies have not identified GNAS mutations in ossifying fibroma. [15][16][17][18] Cytogenetic abnormalities such as supernumerary ring chromosomes, including amplification of chromosome 12q13-15 leading to multiple copies of MDM2, characterize low-grade osteosarcoma.…”

“…14,15 Recent studies have not identified GNAS mutations in ossifying fibroma. [15][16][17][18] Cytogenetic abnormalities such as supernumerary ring chromosomes, including amplification of chromosome 12q13-15 leading to multiple copies of MDM2, characterize low-grade osteosarcoma. [19][20][21] To differentiate low-grade osteosarcoma from other fibro-osseous lesions, several studies have shown the diagnostic value of detecting overexpression of MDM2 by immunohistochemistry, 22,23 and MDM2 amplification by quantitative real-time PCR (qPCR), comparative genomic hybridization (CGH) array, or fluorescence in situ hybridization (FISH).…”

GNAS mutations are not detected in parosteal and low-grade central osteosarcomas

“…[7][8][9] Bone tumors analyzed previously for GNAS alterations include fibrous dysplasia (N = 405), [10][11][12][13][14][15][16] ossifying fibroma (N = 65), 10,12,[15][16] osteofibrous dysplasia (N = 19), 10,12-13 low-grade central osteosarcoma (N = 12) 10,13-14 , and parosteal osteosarcoma (N = 10). 10 GNAS mutations have been reported in fibrous dysplasia and have not been described until recently in any other fibrous osseous lesions with the exception of a single low-grade central osteosarcoma. 14 These reported GNAS mutations in fibrous dysplasia include p.R201C, 13 p.R201H, 13 p.R201S, 17 and p.Q227L.…”