Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors

// Guhyun Kang 1,8,* Hongseok Yun 1,2,* , Choong-Hyun Sun 2 , Inho Park 2 , Seungmook Lee 2 , Jekeun Kwon 2 , Ingu Do 1,3,4 , Min Eui Hong 1,4,9 , Michael Van Vrancken 1 , Jeeyun Lee 5 , Joon Oh Park 5 , Jeonghee Cho 6 , Kyoung-Mee Kim 1,4 and Tae Sung Sohn 7 1 Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea 3 Samsung Cancer Research Institute, Samsung Medical Center, Seoul, Korea 4 Center for Cancer Companion Diagnostics, Samsung Medical Center, Seoul, Korea 5 Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea 7 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Pathology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea 9 Current address: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Kyoung-Mee Kim, email: // Tae Sung Sohn, email: // Keywords : high-throughput nucleotide sequencing; gastrointestinal stromal tumor; exome; transcriptome Received : January 30, 2015 Accepted : March 10, 2015 Published : March 30, 2015 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.