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

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

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 g...

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Main Authors: Kang, Guhyun, Yun, Hongseok, Sun, Choong-Hyun, Park, Inho, Lee, Seungmook, Kwon, Jekeun, Do, Ingu, Hong, Min Eui, Van Vrancken, Michael, Lee, Jeeyun, Park, Joon Oh, Cho, Jeonghee, Kim, Kyoung-Mee, Sohn, Tae Sung
Format: Online
Language:English
Published: Impact Journals LLC 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872731/
id pubmed-4872731
recordtype oai_dc
spelling pubmed-48727312016-05-25 Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors Kang, Guhyun Yun, Hongseok Sun, Choong-Hyun Park, Inho Lee, Seungmook Kwon, Jekeun Do, Ingu Hong, Min Eui Van Vrancken, Michael Lee, Jeeyun Park, Joon Oh Cho, Jeonghee Kim, Kyoung-Mee Sohn, Tae Sung Research Paper 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. Impact Journals LLC 2015-03-30 /pmc/articles/PMC4872731/ /pubmed/25987131 http://dx.doi.org/10.18632/oncotarget.3731 Text en Copyright: © 2016 Kang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Kang, Guhyun
Yun, Hongseok
Sun, Choong-Hyun
Park, Inho
Lee, Seungmook
Kwon, Jekeun
Do, Ingu
Hong, Min Eui
Van Vrancken, Michael
Lee, Jeeyun
Park, Joon Oh
Cho, Jeonghee
Kim, Kyoung-Mee
Sohn, Tae Sung
spellingShingle Kang, Guhyun
Yun, Hongseok
Sun, Choong-Hyun
Park, Inho
Lee, Seungmook
Kwon, Jekeun
Do, Ingu
Hong, Min Eui
Van Vrancken, Michael
Lee, Jeeyun
Park, Joon Oh
Cho, Jeonghee
Kim, Kyoung-Mee
Sohn, Tae Sung
Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
author_facet Kang, Guhyun
Yun, Hongseok
Sun, Choong-Hyun
Park, Inho
Lee, Seungmook
Kwon, Jekeun
Do, Ingu
Hong, Min Eui
Van Vrancken, Michael
Lee, Jeeyun
Park, Joon Oh
Cho, Jeonghee
Kim, Kyoung-Mee
Sohn, Tae Sung
author_sort Kang, Guhyun
title Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
title_short Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
title_full Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
title_fullStr Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
title_full_unstemmed Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors
title_sort integrated genomic analyses identify frequent gene fusion events and vhl inactivation in gastrointestinal stromal tumors
description 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.
publisher Impact Journals LLC
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872731/
_version_ 1613581454691794944

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