title: Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics.
abstract: Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases. MAP2K4, AURKA, AURKB, and c-MYC amplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of the TP53 (24%), PTEN (16%), and CDKN2A (20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, including RB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1, and FLT4 genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.
authors.affiliation: University of Washington Medical Center, Department of Anatomic Pathology, Seattle, WA, 98195, USA. Electronic address: jourgeor@uw.edu.
authors.forename: George
authors.initials: G
authors.lastname: Jour
authors.affiliation: University of Washington Medical Center, Department of Laboratory Medicine Seattle, WA, 98195, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Scarborough
authors.affiliation: University of Washington Medical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98195, USA; University of Washington Medical Center Division of Medical Oncology, Seattle, WA, 98195, USA.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Jones
authors.affiliation: University of Washington Medical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98195, USA; University of Washington Medical Center Division of Medical Oncology, Seattle, WA, 98195, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Loggers
authors.affiliation: University of Washington Medical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98195, USA; University of Washington Medical Center Division of Medical Oncology, Seattle, WA, 98195, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Pollack
authors.affiliation: University of Washington Medical Center, Department of Laboratory Medicine Seattle, WA, 98195, USA; University of Washington, Department of Genome Sciences, University of Washington, Seattle, WA, 98195,USA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: University of Washington Medical Center, Department of Anatomic Pathology, Seattle, WA, 98195, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Hoch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010865:Pilot Projects; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
keywords: Molecular profiling; Next generation sequencing; Precision therapeutics; Soft tissue sarcoma; Targetable mutations