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Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study
PURPOSE: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe p...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Cancer Association
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582486/ https://www.ncbi.nlm.nih.gov/pubmed/35038826 http://dx.doi.org/10.4143/crt.2021.1194 |
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author | Kwon, Joonha Lee, Jun Hyeong Lee, Young Han Lee, Jeeyun Ahn, Jin-Hee Kim, Se Hyun Kim, Seung Hyun Kim, Tae Il Yun, Kum-Hee Park, Young Suk Kim, Jeong Eun Lee, Kyu Sang Choi, Jung Kyoon Kim, Hyo Song |
author_facet | Kwon, Joonha Lee, Jun Hyeong Lee, Young Han Lee, Jeeyun Ahn, Jin-Hee Kim, Se Hyun Kim, Seung Hyun Kim, Tae Il Yun, Kum-Hee Park, Young Suk Kim, Jeong Eun Lee, Kyu Sang Choi, Jung Kyoon Kim, Hyo Song |
author_sort | Kwon, Joonha |
collection | PubMed |
description | PURPOSE: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. MATERIALS AND METHODS: We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. RESULTS: Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. CONCLUSION: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor. |
format | Online Article Text |
id | pubmed-9582486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Korean Cancer Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-95824862022-10-26 Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study Kwon, Joonha Lee, Jun Hyeong Lee, Young Han Lee, Jeeyun Ahn, Jin-Hee Kim, Se Hyun Kim, Seung Hyun Kim, Tae Il Yun, Kum-Hee Park, Young Suk Kim, Jeong Eun Lee, Kyu Sang Choi, Jung Kyoon Kim, Hyo Song Cancer Res Treat Original Article PURPOSE: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. MATERIALS AND METHODS: We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. RESULTS: Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. CONCLUSION: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor. Korean Cancer Association 2022-10 2022-01-17 /pmc/articles/PMC9582486/ /pubmed/35038826 http://dx.doi.org/10.4143/crt.2021.1194 Text en Copyright © 2022 by the Korean Cancer Association https://creativecommons.org/licenses/by-nc/4.0/This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Kwon, Joonha Lee, Jun Hyeong Lee, Young Han Lee, Jeeyun Ahn, Jin-Hee Kim, Se Hyun Kim, Seung Hyun Kim, Tae Il Yun, Kum-Hee Park, Young Suk Kim, Jeong Eun Lee, Kyu Sang Choi, Jung Kyoon Kim, Hyo Song Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title | Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title_full | Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title_fullStr | Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title_full_unstemmed | Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title_short | Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study |
title_sort | whole-genome and transcriptome sequencing identified notch2 and hes1 as potential markers of response to imatinib in desmoid tumor (aggressive fibromatosis): a phase ii trial study |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582486/ https://www.ncbi.nlm.nih.gov/pubmed/35038826 http://dx.doi.org/10.4143/crt.2021.1194 |
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