The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases

Lee, Seung Eun; Lee, Eun Hee; Park, Hyuk; Sung, Ji Youn; Lee, Hyoun Wook; Kang, So Young; Seo, S.I.; Kim, Byung Heon; Lee, Hyojin; Seo, An Na; Ahn, Geunghwan; Choi, Yoon–La

doi:10.1016/j.humpath.2011.09.012

Cited by 86 publications

(56 citation statements)

References 21 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P ¼ 0.004), non-juvenile ossifying fibromas (P ¼ 0.001), and all other benign craniofacial fibro-osseous lesions combined (P ¼ 0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

show abstract

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…There are several methods to detect GNAS mutation from paraffin-embedded tissues or frozen samples, ie, Sanger direct sequencing, 39 restriction fragment-length polymorphism from PCR, 11,36,37 an allele-specific probe for PCR quantification, 40 PCR with mutation-specific restriction enzyme digestion, 32 allele-specific PCR, 24 coamplification at lower denaturation temperature PCR, 26 HRM combined with direct sequencing and, more recently, pyrosequencing. 41 The sensitivity of these techniques is variable and GNAS mutations remain unidentified in many fibrous dysplasia lesions, regardless of the molecular method used.…”

mentioning

confidence: 99%

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

et al. 2013

View full text Add to dashboard Cite

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;

show abstract

“…Three of 7 patients with isolated FD were positive for [i]GNAS[/i] mutations (8). In a meta-analysis done by Lee et al (14), 9 studies searching [i]GNAS[/i] mutations in 203 cases of sporadic FD were analyzed. The overall positivity rate for [i]GNA[/i]S mutation was 71.9% (146/203).…”

Section: Discussionmentioning

confidence: 99%

McCune-Albright Syndrome Mimicking Malignancy: an Endocrine Disease From Oncologist’s Perspective

Genc

Özkan²,

Büyükgebiz³

2012

Jcrpe

View full text Add to dashboard Cite

Fibrous dysplasia (FD) is categorized as either monostotic or polyostotic and may occur as a component of McCune-Albright syndrome (MAS). Imaging findings can mimic neoplastic diseases. We present a case of MAS initially suspected to have neoplastic disease. A 9-year-old girl was admitted to pediatric emergency with ataxia. Upon hospitalization, an extradural mass was seen on cranial magnetic resonance imaging (MRI) and the bone survey showed lytic lesions in the long bones. The patient was referred to the pediatric oncology department with a presumptive diagnosis of Langerhans cell histiocytosis or metastatic tumor. Further investigations demonstrated that the patient had MAS and coexisting postinfectious cerebellitis. The findings in this patient demonstrate that the radiographic findings and the clinical presentation of FD and MAS may be similar to those of malignant diseases. Conflict of interest:None declared.

show abstract

The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases

Cited by 86 publications

References 21 publications

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

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

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

McCune-Albright Syndrome Mimicking Malignancy: an Endocrine Disease From Oncologist’s Perspective

Contact Info

Product

Resources

About