Establishment of risk stratification based on genetic mutation in pediatric Langerhans cell histiocytosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K07828
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Jichi Medical University
• Principal Investigator: Morimoto Akira 自治医科大学, 医学部, 客員教授 (30326227)
• Co-Investigator(Kenkyū-buntansha): 翁 由紀子 自治医科大学, 医学部, 非常勤講師 (30438650) ; 早瀬 朋美 自治医科大学, 医学部, 客員研究員 (50433587)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: ランゲルハンス細胞組織球症 / 分裂促進因子活性化タンパク質キナーゼ / BRAF V600E変異 / 予後因子

Outline of Final Research Achievements

In a retrospective cohort of 59 patients (50 children, 9 adults), 46% had BRAF V600E mutation. In a prospective cohort of 104 patients (aged <20 years), 40.4% had BRAF V600E mutation, 6.7% had BRAF indel, and 31.7% had MAP2K1 mutation. BRAF V600E mutation was significantly more common in patients with a disease activity score (DAS) of 7 or more (76.9% vs. 38.5%, p=0.014).No association was found between genetic variants and sex, age at diagnosis, disease type, initial treatment response, event-free survival, overall survival, or CNS-related complications in any cohort.
BRAF V600E mutation was associated with DAS but not outcomes of LCH.

Free Research Field

組織球症

Academic Significance and Societal Importance of the Research Achievements

LCH細胞にはMitogen-activated Protein Kinase経路の遺伝子に相互排他的な発がん性変異があることが報告され、BRAF V600E変異は最も高頻度な変異で50%前後の例に見いだされる。欧米では、BRAF V600E変異は、高リスク（高い病勢スコア(DAS)・高い再発率・高い中枢神経関連続発症頻度）と報告されている。しかし、日本のシタラビン中心の治療を受けた患者においては、BRAF V600E変異は、DASが高いこととは関連するが転帰とは関連せず、BRAF V600Eの有無により治療を層別化する意義は低いことが分かった。