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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1240-1255
Number of pages16
JournalCancer Research and Treatment
Volume54
Issue number4
DOIs
StatePublished - Oct 2022

Keywords

  • Clinical trial phase II
  • Computational biology
  • Fibromatosis aggressive
  • Imatinib mesylate
  • Transcriptome
  • Whole-genome sequencing

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