Identifying actionable variants using next generation sequencing in patients with a historical diagnosis of undifferentiated pleomorphic sarcoma

Abstract

There are limited data regarding the molecular characterization of undifferentiated pleomorphic sarcomas (UPS; formerly malignant fibrous histiocytoma). This study aimed to investigate the utility of next generation sequencing (NGS) in UPS to identify subsets of patients who harbour actionable mutations. Patients diagnosed with UPS underwent pathological re-evaluation by a pathologist specializing in sarcoma. Tumor DNA was isolated from archived fresh frozen tissue samples and genotyped using NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons). In total, 95 patients initially classified with UPS were identified. Following pathology re-review the histological subtypes were reclassified to include: Myxofibrosarcoma (MFS, N=44); UPS(N=18); and Others (N=27; including undifferentiated spindle cell sarcoma (N=15) and dedifferentiated liposarcoma (N=6)). Seven cases were excluded from further analysis for other reasons. Baseline demographics of the finalized cohort (N=88) showed a median age of 66 years (32-95), primarily with stage I-III disease (92%) and high grade (86%) lesions. Somatic mutations were identified in 31 cases (35%)(Total mutations=36: solitary mutation(n=27); two mutations(n=3); three mutations(n=1)). The most commonly identified mutations were in TP53 (n=24), ATM (n=3) and PIK3CA (n=2). Three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, mainly related to biomarkers of prediction of response, however few had targetable driver mutations. Somatic mutation status did not influence disease free or overall survival. Based on the small number of clinically relevant mutations, this data does not support the routine use of targeted NGS panels outside of research protocols in UPS. This article is protected by copyright. All rights reserved.

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