title: The molecular landscape of extraskeletal osteosarcoma: A clinicopathological and molecular biomarker study.
abstract: Extraskeletal osteosarcoma (ESOSA) is a rare soft tissue neoplasm representing <5% of osteosarcomas and <1% of all soft-tissue sarcomas. Herein, we investigate the clinicopathological and molecular features of ESOSA and explore potential parameters that may affect outcome. Thirty-two cases were retrieved and histomorphology was reviewed. Clinical history and follow-up were obtained through electronic record review. DNA from formalin-fixed paraffin-embedded (FFPE) tissue was extracted and processed from 27 cases. Genome-wide DNA copy number (CN) alterations and allelic imbalances were analyzed by single nucleotide polymorphism array using Affymetrix OncoScan FFPE Assay. Massive high-throughput deep parallel sequencing was performed using a customized panel targeting 410 cancer genes. Log rank, Fisher's exact test and Cox proportional hazards were used for statistical analysis. In this series of 32 patients (male n = 12, female n = 20), the average age was 66 years (19-93) and median follow up was 24 months (range 6-120 months). Frequent genomic alterations included CN losses in tumour suppressor genes including CDKN2A (70%), TP53 (56%) and RB1 (49%). Mutations affecting methylation/demethylation, chromatin remodeling and WNT/SHH pathways were identified in 40%, 27%, and 27%, respectively. PIK3CA and TERT promoter variant mutations were identified in 11% of the cases. Cases harbouring simultaneous TP53 and RB1 biallelic CN losses were associated with worse overall survival and local recurrence (p = 0.04, p = 0.02, respectively). CDKN2A losses and positive margins were also associated with worse overall survival (p = 0.002; p = 0.03, respectively). Our findings suggest that age above 60, positive margin status, simultaneous biallelic TP53 and RB1 losses and CDKN2A loss are associated with a worse outcome in ESOSA. Comparison between conventional paediatric osteosarcoma and ESOSA shows that, while both share genetic similarities, there are notable dissimilarities and mechanistic differences in the molecular pathways involved in ESOSA.
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: George
authors: G
authors: Jour
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Lu
authors: L
authors: Wang
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Sumit
authors: S
authors: Middha
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Ahmet
authors: A
authors: Zehir
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Wen
authors: W
authors: Chen
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Justyna
authors: J
authors: Sadowska
authors: Department of Orthopedic Surgery Memorial Sloan Kettering Cancer Center New York NY USA.
authors: John
authors: J
authors: Healey
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Narasimhan P
authors: NP
authors: Agaram
authors: Department of Orthopedic Surgery Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Lisa
authors: L
authors: Choi
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Khedoudja
authors: K
authors: Nafa
authors: Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA.
authors: Meera
authors: M
authors: Hameed
keywords: SNP array; extraskeletal osteosarcoma; next generation sequencing; osteosarcoma