title: Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. We sequenced nine exomes and transcriptomes, and two genomes of GISTs for integrated analyses. We detected 306 somatic variants in nine GISTs and recurrent protein-altering mutations in 29 genes. Transcriptome sequencing revealed 328 gene fusions, and the most frequently involved fusion events were associated with IGF2 fused to several partner genes including CCND1, FUS, and LASP1. We additionally identified three recurrent read-through fusion transcripts: POLA2-CDC42EP2, C8orf42-FBXO25, and STX16-NPEPL1. Notably, we found intragenic deletions in one of three exons of the VHL gene and increased mRNAs of VEGF, PDGF-β, and IGF-1/2 in 56% of GISTs, suggesting a mechanistic link between VHL inactivation and overexpression of hypoxia-inducible factor target genes in the absence of hypoxia. We also identified copy number gain and increased mRNA expression of AMACR, CRIM1, SKP2, and CACNA1E. Mapping of copy number and gene expression results to the KEGG pathways revealed activation of the JAK-STAT pathway in small intestinal GISTs and the MAPK pathway in wild-type GISTs. These observations will allow us to determine the genetic basis of GISTs and will facilitate further investigation to develop new therapeutic options.
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Department of Pathology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea.
authors.forename: Guhyun
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea.
authors.forename: Hongseok
authors.initials: H
authors.lastname: Yun
authors.affiliation: Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea.
authors.forename: Choong-Hyun
authors.initials: CH
authors.lastname: Sun
authors.affiliation: Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Park
authors.affiliation: Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea.
authors.forename: Seungmook
authors.initials: S
authors.lastname: Lee
authors.affiliation: Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea.
authors.forename: Jekeun
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Samsung Cancer Research Institute, Samsung Medical Center, Seoul, Korea.|Center for Cancer Companion Diagnostics, Samsung Medical Center, Seoul, Korea.
authors.forename: Ingu
authors.initials: I
authors.lastname: Do
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Center for Cancer Companion Diagnostics, Samsung Medical Center, Seoul, Korea.|Current address: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea.
authors.forename: Min Eui
authors.initials: ME
authors.lastname: Hong
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Michael
authors.initials: M
authors.lastname: Van Vrancken
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Jeonghee
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Center for Cancer Companion Diagnostics, Samsung Medical Center, Seoul, Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Sohn
mesh_terms: D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: exome; gastrointestinal stromal tumor; high-throughput nucleotide sequencing; transcriptome