Analysis of driver gene mutations in pulmonary alveolar proteinosis associated with myelodysplastic syndrome.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08547
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kyorin University
• Principal Investigator: Ishii Haruyuki 杏林大学, 医学部, 教授 (30406970)
• Co-Investigator(Kenkyū-buntansha): 田澤 立之 東京医科歯科大学, 学生支援・保健管理機構, 教授 (70301041) ; 竹内 志穂 新潟大学, 医歯学総合研究科, 客員研究員 (70422277) ; 中田 光 新潟大学, 医歯学総合病院, 特任教授 (80207802)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺胞蛋白症 / 骨髄異形成症候群 / 遺伝子変異

Outline of Final Research Achievements

The purpose of this study was to analyze the driver gene mutations of alveolar proteinosis secondary to myelodysplastic syndrome (MDS) in order to elucidate the etiology and pathogenesis of this disease. Because the disease under study is a rare lung disease, the number of new cases available for analysis was unexpectedly low for the three-year period 2020-2022, due in large part to the pandemic of COVID-19. However, analysis of genetic mutations in 13 MDS-SPAP cases was performed and 21 genetic mutations were identified. Of these, U2AF1 and ASXL1 were found in 31% (4/13), followed by TET2, ZRSR2, and STAG2 in 23% (3/13). These are also found as genetic mutations in MDS itself without SPAP, but U2AF1 is about 6-8% frequent in MDS. Therefore, U2AF1, which is associated with RNA splicing, was considered a possible candidate driver gene for MDS-SPAP.

Free Research Field

肺胞蛋白症

Academic Significance and Societal Importance of the Research Achievements

稀少肺疾患であるMDS-SPAPを対象にした集学的研究は少ない。MDS-SPAPは生存期間中央値17か月、2年生存率42%と著しく予後不良な疾患である。これまで我々の研究から、続発性PAP診断時の%DLcoが50%以下、ステロイド治療下が死亡リスク因子として予後予測因子は解明してきたが、病因につながる研究が求められてきた分野である。そのため、今回の研究において症例数は十分ではなかったが、MDS-SPAPのドライバー遺伝子変異の候補はU2AF1を筆頭に、エピジェネシス制御に関わるASXL1が病因に関連している可能性が示唆された結果は、今後のさらなる研究に繋がる成果にはなったと思われる。