Clinical application of biomarker associated with resistance of molecular target therapy for GIST based on comprehensive molecular analysis in a large scale of clinical samples(Fostering Joint International Research)

2019 Fiscal Year Final Research Report

• Project/Area Number: 16KK0184
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: Iwatsuki Masaaki 熊本大学, 大学院生命科学研究部(医), 助教 (50452777)
• Project Period (FY): 2017 – 2019
• Keywords: GIST / 再発高リスク群 / イマチニブ耐性

Outline of Final Research Achievements

Gastrointestinal stromal tumors (GISTs) are rare tumor of the gastrointestinal tract. Although the factors responsible for the malignant and aggressive clinical behavior of GISTs, including tumor size, mitotic index, tumor location, and tumor rupture have been investigated for years, molecular biomarker remain unknown.
We established imatinib-resistant GIST cell and picked up FBXW7 gene by comprehensive molecular analysis. We collected clinical samples by Japan-US collaborative study and examine FBXW7 expression of by immunohistochemical study in 139 high-risk GIST compared with 166 non high-risk GIST. The low FBXW7 group in high-risk GIST showed a significantly poorer prognosis. In 75 cases of high-risk GIST treated with imatinib as adjuvant therapy, the low FBXW7 group showed poorer prognosis. Our study suggests that FBXW7 is a potential prognostic factor of recurrence in high-risk GIST. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely.

Free Research Field

腫瘍外科学

Academic Significance and Societal Importance of the Research Achievements

消化管間質性腫瘍(GIST)は稀少腫瘍であるが、再発をきたす悪性疾患である。現在は腫瘍径などで規定されるリスク分類に従い、イマチニブによる術後補助療法が推奨されているが、様々な有害事象や高額な薬剤でもあるため、適切な患者選択が必要である。
本研究ではがん抑制遺伝子であるFBXW7に着目した。希少腫瘍のため日米共同で約300例のGIST検体を集積し、FBXW7の発現を確認した。とくに高リスク群ではFBXW7低発現が予後を占う因子であった。GISTにおいてFBXW7が再発予測因子であるとともにイマチニブによる補助療法の耐性のバイオマーカーになり、既存のリスク分類を凌駕しうる因子であることが示された。