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Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations

Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and...

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Autores principales: Ohshima, Keiichi, Nagashima, Takeshi, Fujiya, Keiichi, Hatakeyama, Keiichi, Watanabe, Yuko, Morimoto, Kimiko, Kamada, Fukumi, Shimoda, Yuji, Ohnami, Sumiko, Naruoka, Akane, Serizawa, Masakuni, Ohnami, Shumpei, Kenmotsu, Hirotsugu, Shiomi, Akio, Tsubosa, Yasuhiro, Bando, Etsuro, Sugiura, Teiichi, Sugino, Takashi, Terashima, Masanori, Uesaka, Katsuhiko, Urakami, Kenichi, Akiyama, Yasuto, Yamaguchi, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124575/
https://www.ncbi.nlm.nih.gov/pubmed/37377752
http://dx.doi.org/10.1158/2767-9764.CRC-22-0364
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author Ohshima, Keiichi
Nagashima, Takeshi
Fujiya, Keiichi
Hatakeyama, Keiichi
Watanabe, Yuko
Morimoto, Kimiko
Kamada, Fukumi
Shimoda, Yuji
Ohnami, Sumiko
Naruoka, Akane
Serizawa, Masakuni
Ohnami, Shumpei
Kenmotsu, Hirotsugu
Shiomi, Akio
Tsubosa, Yasuhiro
Bando, Etsuro
Sugiura, Teiichi
Sugino, Takashi
Terashima, Masanori
Uesaka, Katsuhiko
Urakami, Kenichi
Akiyama, Yasuto
Yamaguchi, Ken
author_facet Ohshima, Keiichi
Nagashima, Takeshi
Fujiya, Keiichi
Hatakeyama, Keiichi
Watanabe, Yuko
Morimoto, Kimiko
Kamada, Fukumi
Shimoda, Yuji
Ohnami, Sumiko
Naruoka, Akane
Serizawa, Masakuni
Ohnami, Shumpei
Kenmotsu, Hirotsugu
Shiomi, Akio
Tsubosa, Yasuhiro
Bando, Etsuro
Sugiura, Teiichi
Sugino, Takashi
Terashima, Masanori
Uesaka, Katsuhiko
Urakami, Kenichi
Akiyama, Yasuto
Yamaguchi, Ken
author_sort Ohshima, Keiichi
collection PubMed
description Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557–558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557–558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557–558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557–558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557–558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557–558 mutations are associated with increased genomic instability in malignant GISTs. SIGNIFICANCE: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557–558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.
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spelling pubmed-101245752023-04-25 Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations Ohshima, Keiichi Nagashima, Takeshi Fujiya, Keiichi Hatakeyama, Keiichi Watanabe, Yuko Morimoto, Kimiko Kamada, Fukumi Shimoda, Yuji Ohnami, Sumiko Naruoka, Akane Serizawa, Masakuni Ohnami, Shumpei Kenmotsu, Hirotsugu Shiomi, Akio Tsubosa, Yasuhiro Bando, Etsuro Sugiura, Teiichi Sugino, Takashi Terashima, Masanori Uesaka, Katsuhiko Urakami, Kenichi Akiyama, Yasuto Yamaguchi, Ken Cancer Res Commun Research Article Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557–558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557–558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557–558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557–558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557–558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557–558 mutations are associated with increased genomic instability in malignant GISTs. SIGNIFICANCE: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557–558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation. American Association for Cancer Research 2023-04-24 /pmc/articles/PMC10124575/ /pubmed/37377752 http://dx.doi.org/10.1158/2767-9764.CRC-22-0364 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Ohshima, Keiichi
Nagashima, Takeshi
Fujiya, Keiichi
Hatakeyama, Keiichi
Watanabe, Yuko
Morimoto, Kimiko
Kamada, Fukumi
Shimoda, Yuji
Ohnami, Sumiko
Naruoka, Akane
Serizawa, Masakuni
Ohnami, Shumpei
Kenmotsu, Hirotsugu
Shiomi, Akio
Tsubosa, Yasuhiro
Bando, Etsuro
Sugiura, Teiichi
Sugino, Takashi
Terashima, Masanori
Uesaka, Katsuhiko
Urakami, Kenichi
Akiyama, Yasuto
Yamaguchi, Ken
Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title_full Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title_fullStr Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title_full_unstemmed Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title_short Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557–558 Deletion Mutations
title_sort whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring kit exon 11 557–558 deletion mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124575/
https://www.ncbi.nlm.nih.gov/pubmed/37377752
http://dx.doi.org/10.1158/2767-9764.CRC-22-0364
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