Press Release

Mathematical modeling and mutational analysis reveal optimal therapy to prevent malignant transformation in grade II IDH-mutant gliomas

Abstract

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.

Article

Publication:Cancer Research

Title:Mathematical modeling and mutational analysis reveal optimal therapy to prevent malignant transformation in grade II IDH-mutant gliomas

Author:Kosuke Aoki*, Hiromichi Suzuki, Takashi Yamamoto, Kimiyo N Yamamoto, Sachi Maeda, Yusuke Okuno, Melissa Ranjit, Kazuya Motomura, Fumiharu Ohka, Kuniaki Tanahashi, Masaki Hirano, Tomohide Nishikawa, Hiroyuki Shimizu, Yotaro Kitano, Junya Yamaguchi, Shintaro Yamazaki, Hideo Nakamura, Masamichi Takahashi, Yoshitaka Narita, Mitsutoshi Nakada, Shoichi Deguchi, Masahiro Mizoguchi, Yasutomo Momii, Yoshihiro Muragaki, Tatsuya Abe, Jiro Akimoto, Toshihiko Wakabayashi, Ryuta Saito, Seishi Ogawa, Hiroshi Haeno*, and Atsushi Natsume*

DOI:10.1158/0008-5472.CAN-21-0985