153 184

Cited 0 times in

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

 Joonha Kwon  ;  Jun Hyeong Lee  ;  Young Han Lee  ;  Jeeyun Lee  ;  Jin-Hee Ahn  ;  Se Hyun Kim  ;  Seung Hyun Kim  ;  Tae Il Kim  ;  Kum-Hee Yun  ;  Young Suk Park  ;  Jeong Eun Kim  ;  Kyu Sang Lee  ;  Jung Kyoon Choi  ;  Hyo Song Kim 
 CANCER RESEARCH AND TREATMENT, Vol.54(4) : 1240-1255, 2022-10 
Journal Title
Issue Date
Fibromatosis, Aggressive* / drug therapy ; Fibromatosis, Aggressive* / genetics ; Fibromatosis, Aggressive* / pathology ; Humans ; Imatinib Mesylate / pharmacology ; Imatinib Mesylate / therapeutic use ; Mutation ; Prospective Studies ; RNA ; Receptor, Notch2 / genetics ; Retrospective Studies ; Transcription Factor HES-1 / genetics ; Transcription Factor HES-1 / metabolism ; Transcriptome ; beta Catenin / metabolism
Clinical trial phase II ; Computational biology ; Fibromatosis aggressive ; Imatinib mesylate ; Transcriptome ; Whole-genome sequencing
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.
Files in This Item:
T202204649.pdf Download
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seung Hyun(김승현) ORCID logo https://orcid.org/0000-0002-3878-1944
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Kim, Hyo Song(김효송) ORCID logo https://orcid.org/0000-0002-0625-9828
Lee, Young Han(이영한) ORCID logo https://orcid.org/0000-0002-5602-391X
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.