2022 Fiscal Year Final Research Report
Tumor agonistic and tissue specific role of BRAF mutations in cancer
| Project/Area Number |
20H03542
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
Ebi Hiromichi 愛知県がんセンター(研究所), がん標的治療TR分野, 分野長 (00645145)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | BRAF / mutation / molecular classification |
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| Outline of Final Research Achievements |
We performed functional analysis of 106 variants of BRAF with unknown function and identified 17 novel gain-of-function mutations. The reasons for the gain-of-function of these mutations were inferred from the protein sequence, structure, and interactions, and a predictive model of function was constructed. We also performed expression and pathway analyses of colorectal cancer cases with each BRAF mutation, which can be classified into three types based on their functions, and examined the effects of phenotypic differences on tumorigenesis. In addition, we focused on Class I mutant BRAF colorectal cancer and identified candidate molecules that could be responsible for resistance to currently approved inhibitors.
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| Free Research Field |
Translational Research in Oncology
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| Academic Significance and Societal Importance of the Research Achievements |
ゲノム医療特に包括的遺伝子プロファイリング検査が臨床導入され、近年BRAF変異が同定される機会が増えている。それらの多くは機能不明バリアントであることから、本研究により、機能不明バリアントの機能予測が可能になれば、患者の治療法選択に役立てることが可能である。また、BRAF Class 1変異（V600変異）大腸がんについては、現在抗EGFR抗体とBRAF阻害薬の併用療法がされているが、30%程度の患者に奏効するのみである。本研究ではパスウエイ解析の結果、Class 1変異が2種類に分類される結果が得られており、今後阻害薬の効果との関連を明らかにすることで、新たな治療法を提唱できる可能性がある。
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