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: Guhyun Kang, Hongseok Yun, Choong-Hyun Sun, Inho Park, Seungmook Lee, Jekeun Kwon, Ingu Do, Min Eui Hong, Michael Van Vrancken, Jeeyun Lee, Joon Oh Park, Jeonghee Cho, Kyoung-Mee Kim, Tae Sung Sohn
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 6 Pg. 6538-51 (Feb 09 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 25987131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oncogene Proteins, Fusion
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• DNA Copy Number Variations
• Exome (genetics)
• Exons (genetics)
• Gastrointestinal Neoplasms (genetics)
• Gastrointestinal Stromal Tumors (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Genomics (methods)
• Genotype
• Humans
• Mutation (genetics)
• Oncogene Proteins, Fusion (genetics)
• Signal Transduction
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)