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

Abstract

Parosteal osteosarcoma, low-grade central osteosarcoma, and fibrous dysplasia share similar histological features that may pose a diagnostic challenge. The detection of GNAS mutations in primary bone tumors has been useful in clinical practice for diagnosing fibrous dysplasia. However, the recent report of GNAS mutations being detected in a significant proportion of parosteal osteosarcoma challenges the specificity of this mutation. As the number of cases reported in this study was small we set out to determine if these results could be reproduced. We studied 97 formalin-fixed paraffin-embedded low-grade osteosarcomas from 90 patients including 62 parosteal osteosarcomas, of which MDM2 amplification was detected in 79%, 11 periosteal osteosarcomas and 24 low-grade central osteosarcoma samples. The mutational status of GNAS was analyzed in codons p.R201, p.Q227, and other less common GNAS alterations by bidirectional Sanger sequencing and/or next generation sequencing using the Life Technologies Ion Torrent platform. GNAS mutations were not detected in any of the low-grade osteosarcomas from which informative DNA was extracted. Our findings therefore support prior observations that GNAS mutations are highly specific for fibrous dysplasia and occur rarely, if ever, in parosteal and other low-grade osteosarcomas. Parosteal and low-grade central osteosarcomas are rare low-grade primary malignant bone tumors comprising o4% of all osteosarcomas. In contrast, fibrous dysplasia is one of the most common benign fibro-osseous tumor-like lesions in medullary bone. Morphologically, there is considerable overlap between these lesions all showing variably shaped bony trabeculae surrounded by spindled-shaped cells, with little to no cytologic atypia. 1 In the majority of cases, imaging studies can easily differentiate parosteal osteosarcoma from fibrous dysplasia and central low-grade osteosarcoma: parosteal osteosarcoma is a surface tumor that may secondarily invade bone marrow, and low-grade central osteosarcoma and fibrous dysplasia are centrally based. Occasionally, fibrous dysplasia arises eccentrically in the marrow space, presenting as an exophytic surfacebased lesion. Such lesions are referred to as fibrous dysplasia protuberans. 2 Hence, distinguishing fibrous dysplasia protuberans from parosteal osteosarcoma can be challenging and differentiating between lowgrade central osteosarcoma and fibrous dysplasia can also be difficult.Parosteal osteosarcoma typically harbors one or more supernumerary ring chromosomes with amplification of the MDM2, SAS, and CDK4 genes. 3,4 MDM2 amplification is reported to occur in 93% (14/15) of low-grade central osteosarcomas 3,5 and in 79% (68/86) of parosteal osteosarcomas. 5,6 Dedifferentiated parosteal osteosarcoma is a distinct tumor variant in which a (high-grade) sarcoma coexists with a conventional parosteal osteosarcoma. Dedifferentiation affects 16-43% of parosteal osteosarcomas

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

“…This prompted a follow‐up study of 97 osteosarcoma samples, 97 samples including 62 parosteal osteosarcomas and 24 low‐grade osteosarcomas which failed to reveal GNAS alterations. Our results supported the previous observations that GNAS mutations are highly specific for fibrous dysplasia and not detected in parosteal osteosarcoma …”

“…Our results supported the previous observations that GNAS mutations are highly specific for fibrous dysplasia and not detected in parosteal osteosarcoma. 15 Despite substantial research efforts, in the majority of cases the cause of osteosarcoma is not known (see below), and the diagnosis, subtyping, and grading remain defined by morphology alone. There are no recurrent genetic alterations or molecular profiles linking the prognosis of patients or their response to chemotherapy (other than the presence of MDM2 amplification, see above), and notably survival rates have not improved significantly over the last three decades.…”

Malignant transformation of craniomaxillofacial fibro‐osseous lesions: A systematic review

“…Recently, Sugiura et al also confirmed the presence of GNAS mutation in an osteosarcoma derived from FD in the hips. Other studies have previously demonstrated that GNAS mutations are not detected in conventional osteosarcomas . Combining these data suggest that a positive GNAS mutation status is highly diagnostic for FD and also for FD‐derived osteosarcoma.…”

Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers

“…While the incidence of MDM2 alterations were similar between the alveolar and embryonal RMS subtypes [15,16], TP53 mutations usually occurred in PAX fusion negative RMS but in generally less than 15% of those cohorts [17,18]. In OS, MDM2 amplifications could be detected in up to 83% of patient samples in individual reports and were more frequent in the parosteal subtype [19,20]. However, TP53 mutations were also prevalent in this histology, with 50e75% of patient tumour samples having at least one inactivating aberration [6,21].…”