Integrated genetic and epigenetic analysis of myxofibrosarcoma

• DOI: 10.1038/s41467-018-03891-9
• Publication Date: 2018-07-11T10:04:06Z
• Authors: Koichi Ogura; Fumie Hosoda; Yasuhito Arai; Hiromi Nakamura; Natsuko Hama; Yasushi Totoki; Akihiko Yoshida; Momoko Nagai; Mamoru Kato; Erika Arakawa; Wakako Mukai; Hirofumi Rokutan; Akira Kawai; Sakae Tanaka; Tatsuhiro Shibata
• Keywords: Proto-Oncogene Proteins B-raf; Monosaccharide Transport Proteins; Oncogene Proteins, Fusion; Science; Fibrosarcoma; Mice, Nude; Fibroma; Article; Epigenesis, Genetic; Cohort Studies; Mice; 03 medical and health sciences; Animals; Humans; Receptor, trkA; 0303 health sciences; Neurofibromin 1; Q; Janus Kinase 1; Survival Analysis; 3. Good health; Gene Expression Regulation, Neoplastic; Genes, cdc; Mutation; Heterografts; Tumor Suppressor Protein p53

AbstractMyxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes includingATRX,JAK1,NF1,NTRK1, and novel oncogenicBRAFfusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS.