A sensitive mutation‐specific screening technique for <i>GNAS1</i> mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone

Idowu, Bernadine; Al-Adnani, Mudher; O’Donnell, Paul; Liu, Yu; Odell, Edward; Diss, TC; Gale, Rosemary E.; Flanagan, Adrienne M.

doi:10.1111/j.1365-2559.2007.02676.x

Cited by 100 publications

(88 citation statements)

References 34 publications

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“…8 Control material included 10 cases of osteofibrous dysplasia that has been previously reported as not harbouring GNAS1 mutations when screened by conventional PCR and mutation-specific restriction enzyme digestion (MSRED). 1 In addition, DNA samples from 30 formalin-fixed paraffin-embedded lymphomas known to have relatively poor quality nucleic acid with variable degrees of DNA degradation and yield, which had been previously analysed in other studies, were analysed for the GNAS1 mutations by COLD-PCR. The purpose of this was to determine whether false-positive results would be generated from such material due to Taq polymerase errors that may occur in low quality or quantity template.…”

Section: Clinical Information Tumour and Control Materials Selectionmentioning

confidence: 99%

“…It can be helpful in distinguishing morphologically similar neoplasms, such as superficial fibromatosis and low-grade fibromyxoid sarcoma from desmoid-type fibromatosis, and reactive fibrous proliferation from fibrous dysplasia. 1,2 More recently, mutation detection has been found to be an important predictive factor in response to antitumourigenic agents. Specifically, it has been shown that the detection of a K-RAS mutation is a predictor of resistance to therapy directed against the receptor tyrosine kinase, EGFR, in large bowel adenocarcinoma and non-small cell lung carcinoma.…”

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confidence: 99%

“…8 However, it was only in 2000, that the same GNAS1 mutations were detected in intramuscular myxoma, and to date, there have only been seven reported cases: two (one R201H and one R201C) of these occurred as non-syndromic cases and five (four R201H and one R201C) occurred as part of Mazabraud's syndrome. 1,9 Intramuscular myxomas are generally hypocellular and hypovascular neoplasms composed of spindle and stellate cells, exhibiting minimal nuclear atypia, embedded within a myxoid stroma. 10 These tumours can be difficult to distinguish from low-grade myxofibrosarcoma, particularly the cellular variant, as neither have a genetic signature and both have a non-specific immunohistochemical profile and show variable expression of smooth muscle actin, and are typically negative for S100.…”

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GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

Delaney

Diss²,

Presneau

et al. 2009

Modern Pathology

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Mutation detection plays an important role in diagnostic pathology, not only in providing a tissue diagnosis, but also in predicting response to antitumourigenic agents. However, mutation detection strategies are often hampered by masking of mutant alleles by wild-type sequences. Coamplification at lower denaturation temperature PCR (COLD-PCR) reportedly increases the proportion of rare variant sequences in a wild-type background by using PCR cycles in which the denaturation temperature is reduced to favour product formation with lower melt temperatures and heteroduplexes arising from minor variants. Intramuscular myxoma is a rare benign soft tissue neoplasm that occurs sporadically and less commonly in association with fibrous dysplasia (Mazabraud's syndrome). Fibrous dysplasia results from activating GNAS1 mutations, and the same mutations have been identified in small numbers of intramuscular myxoma. The aim of the study was primarily to establish whether COLD-PCR is more sensitive than conventional PCR; this was achieved by testing for GNAS1 mutations in intramuscular myxomas using the two methodologies. Mutations were detected in 8 of 28 (29%) cases of intramuscular myxomas using conventional PCR followed by mutation-specific restriction enzyme digestion (PCR-MSRED) whereas 17 of 28 (61%) mutations were detected using COLD-PCR/MSRED. Mutations were detected in two cases where a diagnosis of low-grade myxofibrosarcoma had been favoured over intramuscular myxoma. No mutations were detected in an additional 9 low-grade and 19 high-grade myxofibrosarcomas, and another 40 control samples. This study shows the power of COLD-PCR compared with conventional PCR in mutation detection, and shows that GNAS1 mutation detection increases diagnostic accuracy when distinguishing between intramuscular myxoma and low-grade myxofibrosarcoma.

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Section: Clinical Information Tumour and Control Materials Selectionmentioning

confidence: 99%

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confidence: 99%

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GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

Delaney

Diss²,

Presneau

et al. 2009

Modern Pathology

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“…All of these studies examined the exon 8 of GNAS, six of which also studied the exon 9. [17][18][19]21,23,34 One study examined the exon 7, as well as exons 10-13. 19 Totally, the overall positive rate of GNAS mutation in fibrous dysplasia was 86%.…”

Section: Gnas Mutationsmentioning

confidence: 99%

“…In the 13 studies that mentioned the types of the bone involved, 1,13,16,17,19,21,23,27,28,30,31,33,34 the positive rate of GNAS mutation was 84% in the extragnathic bones and 78% in the craniofacial bones.…”

Section: Gnas Mutationsmentioning

confidence: 99%

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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Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations

et al. 2021

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Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi-institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre-operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high-grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard-of-care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS.

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A sensitive mutation‐specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone

Abstract: Detection of GNAS1 mutations by MSRED is a valuable adjunct to the histopathological diagnosis of FD. This is the first report of a Q227L mutation in FD, although it has been previously documented in pituitary adenoma.

Cited by 100 publications

References 34 publications

GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

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

Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations

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