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
| العنوان: | 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 |
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| المؤلفون: | Jin-Hee Ahn, Hyo Song Kim, Young Suk Park, Jun Hyeong Lee, Kum-Hee Yun, Young Han Lee, Seung Hyun Kim, Tae Il Kim, Jeong Eun Kim, Se Hyun Kim, Kyu Sang Lee, Jeeyun Lee, Jung Kyoon Choi, Joonha Kwon |
| المصدر: | Cancer Research and Treatment. 54:1240-1255 |
| بيانات النشر: | Korean Cancer Association, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Trial study, Imatinib, Biology, medicine.disease, Genome, Transcriptome Sequencing, Fibromatosis, Aggressive, Oncology, Aggressive fibromatosis, Mutation, medicine, Cancer research, Imatinib Mesylate, Humans, RNA, Transcription Factor HES-1, Prospective Studies, Receptor, Notch2, HES1, Transcriptome, beta Catenin, medicine.drug, Retrospective Studies |
| الوصف: | Background: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to efficiently treat desmoid tumor. However, molecular mechanism of why imatinib works remains poorly understood. Here, we describe the potential roles of NOTCH2 and HES1 in association with clinical response to imatinib as in genome and transcriptome levels. Methods: We identified all somatic mutations in coding and non-coding regions via whole genome sequencing using desmoid tumor samples. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale Whole-genome sequencing (WGS) and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, 4 (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 significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on PCAWG data analyses, NOTCH2 mutations affect its 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 responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders Conclusions: 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, which provides an important therapeutic consideration for desmoid tumor. Trial Registration: ClinicalTrials.gov, NCT02495519, Registered July 13, 2015- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02495519Test |
| تدمد: | 2005-9256 1598-2998 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::baa00e8653a5834e3ccdf4dfa25a3ff7Test https://doi.org/10.4143/crt.2021.1194Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....baa00e8653a5834e3ccdf4dfa25a3ff7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20059256 15982998 |
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