Analysis of GNAS mutations in cemento-ossifying fibromas and cemento-osseous dysplasias of the jaws

Patel, Milan M.; Wilkey, Jonathan F.; Abdelsayed, Rafik; D’Silva, Nisha J.; Malchoff, Carl D.; Mallya, Sanjay M.

doi:10.1016/j.tripleo.2009.12.016

Cited by 39 publications

(27 citation statements)

References 19 publications

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“…The approximate frequency of these mutations was comparable to published data. [2][3][4][5][6][7][8][9][13][14][15][16][17][18][19] Twelve of 24 fibrous dysplasia cases were further tested by a general sequencing method. Ten of 12 cases of mutation detected by pyrosequencing assay were confirmed with general sequencing.…”

Section: Resultsmentioning

confidence: 99%

“…2,3 A somatic mutation at codon 201 of the ␣ subunit of G protein (Gs␣), encoded by the GNAS gene, has been identified in FD (monostotic and polyostotic forms) and in multiple endocrinopathies of McCune-Albright syndrome, 4 but is specifically absent in other BFOLs, such as osteofibrous dysplasia. 3,5,6 Point mutations result in replacement of Arg (CGT) at position 201 with, most commonly, His (CAT) or Cys (TGT) 4 ; and in rare cases, with Ser (AGT), 7 Leu (CTT), 8 or Gly (GGT).…”

Section: Benign Fibro-osseous Lesions (Bfols) Frequently Display Overmentioning

confidence: 99%

“…The two most widely used methods are direct sequencing and restriction fragment length polymorphism (RFLP). [2][3][4][5][6][7][8][9][11][12][13][14] Allele-specific oligo hybridization with fluorescent probe 15 instead of radioactive probe 16,17 is also used for quantitative studies. However, this technique requires at least three pairs of labeled probes to detect only the two common mutation types.…”

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confidence: 99%

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Quantitative Analysis of Activating Alpha Subunit of the G Protein (Gsα) Mutation by Pyrosequencing in Fibrous Dysplasia and Other Bone Lesions

Liang

Wei

Hodge

et al. 2011

The Journal of Molecular Diagnostics

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Benign fibro-osseous lesions (BFOLs) frequently display overlapping histological features. The differentiation of fibrous dysplasia (FD) from other BFOLs can be difficult, even for experienced orthopedic pathologists. Accurately distinguishing FD from other BFOLs may have significant clinical and treatment implications. A somatic mutation in gene GNAS encoding the ␣ subunit of the G protein (Gs␣) involving the codon corresponding to Arg 201 has been identified in FD and is specifically absent in other BFOLs. We have developed a quantitative assay by pyrosequencing that has a detection sensitivity of 95%. The test allows the identification of the two most common types of mutation (Arg¡His and Arg¡Cys) in a single reaction, with the ability to analyze other rare mutations. Of the 24 FD cases in this series, 23 (96%) were positive for GNAS/Gs␣ mutation. Nineteen of 23 positive cases exhibited a G¡A mutation (Arg¡His), whereas four had a C¡T mutation (Arg¡Cys). One of three BFOL, not otherwise specified cases was positive for G¡A mutation. None of the osteofibrous dysplasia, ossifying fibromas, or other bone lesions were positive for this mutation. Our experience is that pyrosequencing is an easy and accurate quantification method for Gs␣ mutation detection in fibrous dysplasia. Mutation analysis of the Gs␣ by pyrosequencing has significant potential for improving discrimination between FD and other BFOLs in problematic cases. Fibrous dysplasia is a benign fibro-osseous lesion (BFOL) of the medullary cavity, which may involve one or more bones.1 Because fibrous dysplasia (FD) and other BFOLs frequently display overlapping histological features, differentiation of FD from a BFOL can be difficult, even for experienced orthopedic pathologists, particularly on small biopsy samples.2,3 A somatic mutation at codon 201 of the ␣ subunit of G protein (Gs␣), encoded by the GNAS gene, has been identified in FD (monostotic and polyostotic forms) and in multiple endocrinopathies of McCune-Albright syndrome, 4 but is specifically absent in other BFOLs, such as osteofibrous dysplasia.3,5,6 Point mutations result in replacement of Arg (CGT) at position 201 with, most commonly, His (CAT) or Cys (TGT) 4 ; and in rare cases, with Ser (AGT), 7 Leu (CTT), 8 or Gly (GGT). 9The mutated Gs␣ is constitutively activated, leading to cAMP activation and downstream physiological responses in affected tissues, including bone, skin, endocrine glands, and other tissues. 4,10,11 Because of the mosaic nature of this mutation, the distribution of mutant cells and the ratio of mutant to normal cells in a lesion or affected individual may be reflected in the severity of phenotypic expression.10,11 Interestingly, the percentage of mutant stem cells decreases as a lesion ages resulting in "normalization" of FD of bone.12 Addressing these issues require an extremely sensitive and accurate quantitative assay for Arg201 mutation detection.Many detection assays have been developed to identify the Arg201 mutations. The two most widely used methods are direct ...

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Section: Resultsmentioning

confidence: 99%

Section: Benign Fibro-osseous Lesions (Bfols) Frequently Display Overmentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative Analysis of Activating Alpha Subunit of the G Protein (Gsα) Mutation by Pyrosequencing in Fibrous Dysplasia and Other Bone Lesions

Liang

Wei

Hodge

et al. 2011

The Journal of Molecular Diagnostics

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“…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).…”

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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

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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.

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“…13 Somatic mutations at Arg 201 and Gln 227 codon of Gsa have been identified in many fibrous dysplasia lesions, but absent in ossifying fibroma lesions, 14,15 which points to a possible role of the mutational analysis in differentiating these two conditions. Furthermore, Toyosawa's study also suggest that polymerase chain reaction (PCR) analysis with peptide nucleic acid (PNA) for GNAS mutations at the Arg 201 codon is a useful method to differentiate between fibrous dysplasia and ossifying fibroma.…”

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GNAS mutational analysis in differentiating fibrous dysplasia and ossifying fibroma of the jaw

Shi

Zhang

et al. 2013

Modern Pathology

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Differential diagnosis of fibrous dysplasia and ossifying fibroma may often pose problems for pathologists. The purpose of this study was to evaluate the value of mutational analysis of the GNAS gene in differentiating these two conditions. DNA samples from patients with fibrous dysplasia (n ¼ 30) and ossifying fibroma (n ¼ 21) were collected to analyze the presence of GNAS mutations at exons 8 and 9, the two previously reported hotspot regions, using polymerase chain reaction and direct sequencing. In all, 90% (27/30) of cases with fibrous dysplasia showed missense mutations of codon 201 at exon 8, with a predilection of arginine-to-histidine substitution (p.R201H, 70%) as opposed to arginine-to-cysteine substitution (p.R201C, 30%), whereas no mutation was detected at exon 9. No mutation was found in all 21 cases with ossifying fibroma. In addition, a meta-analysis of previously published reports on GNAS mutations in fibrous dysplasia and ossifying fibroma was performed to substantiate our findings. A total of 24 reports including 307 cases of fibrous dysplasia and 23 cases of ossifying fibroma were reviewed. The overall incidence of GNAS mutations in fibrous dysplasia was 86% (264/307), and the major types of mutations were also R201H (53%) and R201C (45%). No GNAS mutation was detected in all patients with ossifying fibroma. We also reported one case with uncertain diagnosis due to overlapping clinicopathological features of fibrous dysplasia and ossifying fibroma. An R201H mutation was detected in this case, thus confirming a diagnosis of fibrous dysplasia. Taken together, our findings indicate that mutational analysis of GNAS gene is a reliable adjunct to differentiate ossifying fibroma and fibrous dysplasia of the jaws.

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Analysis of GNAS mutations in cemento-ossifying fibromas and cemento-osseous dysplasias of the jaws

Cited by 39 publications

References 19 publications

Quantitative Analysis of Activating Alpha Subunit of the G Protein (Gsα) Mutation by Pyrosequencing in Fibrous Dysplasia and Other Bone Lesions

Quantitative Analysis of Activating Alpha Subunit of the G Protein (Gsα) Mutation by Pyrosequencing in Fibrous Dysplasia and Other Bone Lesions

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

GNAS mutational analysis in differentiating fibrous dysplasia and ossifying fibroma of the jaw

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