The Desmoid Tumor Research Foundation

January 2022

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

Author Information

Kwon J (1), Lee JH (1), Lee YH (2), Lee J (3), Ahn J (4), Kim SH (5), Kim SH (6), Kim TI (7), Yun K (8), Park YS (3), Kim JE (4), Lee KS (9), Choi JK (1), Kim HS (8,10).

(1) Department of Bio and Brain Engineering, KAIST, Daejeon, Korea. (2) Department of Radiology, Yonsei University College of Medicine, Seoul, Korea. (3) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (4) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. (5) Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. (6) Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea. (7) Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. (8) Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. (9) Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea. (10) Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Publication

Cancer Res Treat

Summary

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, 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 non-coding 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, 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 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. 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.

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