Journal Article

Integrated genetic and epigenetic analysis of myxofibrosarcoma

Nakamura, Hiromi, Kawai, Akira, Arai, Yasuhito, Rokutan, Hirofumi, Hosoda, Fumie, Tanaka, Sakae, Ogura, Koichi, Totoki, Yasushi, Hama, Natsuko, Nagai, Momoko, Mukai, Wakako, Kato, Mamoru, Yoshida, Akihiko, Arakawa, Erika, Shibata, Tatsuhiro

2018

Overview

Myxofibrosarcoma (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 including ATRX , JAK1 , NF1 , NTRK1 , and novel oncogenic BRAF fusion 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. Myxofibrosarcoma occurs in adults and is associated with high local relapse. Here, based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/61 / 45/91 / 631/208/69 / 631/67/1798 / Animals / Cell cycle / Cohort Studies / DNA methylation / Epigenesis, Genetic / Epigenetics / Fibroma - genetics / Fibroma - metabolism / Fibroma - mortality / Fibroma - pathology / Fibrosarcoma - genetics / Fibrosarcoma - metabolism / Fibrosarcoma - mortality / Fibrosarcoma - pathology / Fusion protein / Gene Expression Regulation, Neoplastic / Gene sequencing / Genes / Genes, cdc / Genetic analysis / Heterografts / Humanities and Social Sciences / Humans / Immune system / Janus kinase / Janus Kinase 1 - genetics / Janus Kinase 1 - metabolism / Methylation / Mice / Mice, Nude / Monosaccharide Transport Proteins - genetics / Monosaccharide Transport Proteins - metabolism / multidisciplinary / Mutation / Neurofibromin 1 - genetics / Neurofibromin 1 - metabolism / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / p53 Protein / Precision medicine / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Receptor, trkA - genetics / Receptor, trkA - metabolism / Ribonucleic acid / RNA / Sarcoma / Science / Science (multidisciplinary) / Soft tissue sarcoma / Survival Analysis / Therapeutic applications / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Whole Exome Sequencing / X-linked Nuclear Protein - genetics / X-linked Nuclear Protein - metabolism