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

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 NakadaShoichi Deguchi, Masahiro Mizoguchi, Yasutomo Momii, Yoshihiro Muragaki, Tatsuya Abe, Jiro Akimoto, Toshihiko Wakabayashi, Ryuta Saito, Seishi Ogawa, Hiroshi Haeno, Atsushi Natsume

Research output: Contribution to journalArticlepeer-review

Abstract

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut- LGG) 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 genomewide 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 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 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, PI3K 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.

Original languageEnglish
Pages (from-to)4861-4873
Number of pages13
JournalCancer Research
Volume81
Issue number18
DOIs
Publication statusPublished - Sep 15 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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