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

Guhyun Kang,Jeeyun Lee,Min Eui Hong,Hongseok Yun,Tae Sung Sohn,Inho Park,Michael Van Vrancken,Jekeun Kwon,Joon Oh Park,Choong-Hyun Sun,Ingu Do,Jeonghee Cho,Seungmook Lee,Kyoung-Mee Kim

doi:10.18632/oncotarget.3731

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.

Highlights

Gastrointestinal stromal tumors (GISTs) arise from the mesenchymal tissue of the gastrointestinal tract or, rarely, from intra-abdominal soft tissue [1]
Most GISTs harbor gain-of-function mutations in KIT (75-80%) or PDGFRA (~10%) [2, 3]. The discovery of these activating mutations has led to the clinical use of the tyrosine kinase inhibitor imatinib mesylate in patients with advanced or www.impactjournals.com/oncotarget metastatic GISTs [4, 5]
KIT exon 9 mutant or wild-type GISTs show a diminished response to imatinib compared with KIT exon 11 mutants, and GISTs with the PDGFRA D842V mutation show no response [6,7,8]

Summary

Introduction

Gastrointestinal stromal tumors (GISTs) arise from the mesenchymal tissue of the gastrointestinal tract or, rarely, from intra-abdominal soft tissue [1]. These included two recurrently mutated genes (HNRNPCL1 and USP8) identified in a prior study by targeted exome sequencing of 13 GISTs [19]. Previous gene expression analyses showed a lower mRNA level of SDHB in this case compared to KIT-mutant GISTs [27].

Results

Conclusion