ムラガキ　ヨシヒロ   Muragaki Yoshihiro   村垣　善浩    所属   医学部 医学科（東京女子医科大学病院）    職種   客員教授
論文種別	総説
言語種別	英語
査読の有無	査読あり
表題	Mathematical modeling and mutational analysis reveal optimal therapy to prevent malignant transformation in grade II IDH-mutant gliomas.
掲載誌名	正式名：Cancer research 略　 称：Cancer Res ISSNコード：15387445/00085472
掲載区分	国外
巻・号・頁	81(18),pp.4861-4873
著者・共著者	AOKI Kosuke †, SUZUKI Hiromichi , YAMAMOTO Takashi , YANANOTO Kimiyo N , MAEDA Sachi , OKUNO Yusuke, RANJIT Melissa, MOTOMURA Kazuya, OHKA Fumiharu, TANAHASHI Kuniaki , HIRANO Masaki , NISHIKAWA Tomohide, SHIMIZU Hiroyuki , KITANO Yotaro , YAMAGUCHI Junya , YAMAZAKI Shintaro, NAKAMURA Hideo, TAKAHASHI Masamichi , NARITA Yoshitaka , NAKADA Mitsutoshi , DEGUCHI Shoichi , MIZOGUCHI Masahiro , MOMII Yasutomo, MURAGAKI Yoshihiro, ABE Tatsuya , AKIMOTO Jiro, WAKABAYASHI Toshihiko , SAITO Ryuta , OGAWA Seishi , HAENO Hiroshi , NATSUME Atsushi
発行年月	2021/07
概要	WHO grade II isocitrate dehydrogenase mutant gliomas (IDHmut-LGGs) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8-2.8 times compared to before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs ({less than or equal to} 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, phosphoinositide 3-kinase mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.
DOI	10.1158/0008-5472.CAN-21-0985
PMID	34333454