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

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

Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas

Cancer Res. 2021 Sep 15;81(18):4861-4873. doi: 10.1158/0008-5472.CAN-21-0985. Epub 2021 Jul 31.

Authors

Kosuke Aoki^{1

2}, Hiromichi Suzuki³, Takashi Yamamoto³, Kimiyo N Yamamoto⁴, Sachi Maeda³, Yusuke Okuno^{5

6}, Melissa Ranjit³, Kazuya Motomura³, Fumiharu Ohka³, Kuniaki Tanahashi³, Masaki Hirano³, Tomohide Nishikawa³, Hiroyuki Shimizu³, Yotaro Kitano³, Junya Yamaguchi³, Shintaro Yamazaki³, Hideo Nakamura^{7

8}, Masamichi Takahashi⁹, Yoshitaka Narita⁹, Mitsutoshi Nakada¹⁰, Shoichi Deguchi¹¹, Masahiro Mizoguchi¹², Yasutomo Momii¹³, Yoshihiro Muragaki¹⁴, Tatsuya Abe¹⁵, Jiro Akimoto¹⁶, Toshihiko Wakabayashi³, Ryuta Saito³, Seishi Ogawa¹⁷, Hiroshi Haeno¹⁸, Atsushi Natsume^{1

2}

Affiliations

¹ Department of Neurosurgery, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan. aoki-ngy@umin.ac.jp haeno@edu.k.u-tokyo.ac.jp anatsume@med.nagoya-u.ac.jp.
² Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Aichi, Japan.
³ Department of Neurosurgery, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
⁴ Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Takatsuki-shi, Osaka, Japan.
⁵ Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi, Japan.
⁶ Department of Virology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
⁷ Department of Neurosurgery, Kumamoto University, Kumamoto, Japan.
⁸ Department of Neurosurgery, Kurume University, Kurume, Fukuoka, Japan.
⁹ Department of Neurosurgery and Neuro-oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Department of Neurosurgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
¹¹ Division of Neurosurgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
¹² Department of Neurosurgery, Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan.
¹³ Department of Neurosurgery, Oita University, Yufu, Oita, Japan.
¹⁴ Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
¹⁵ Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan.
¹⁶ Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan.
¹⁷ Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁸ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan. aoki-ngy@umin.ac.jp haeno@edu.k.u-tokyo.ac.jp anatsume@med.nagoya-u.ac.jp.

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 (IDH^mut/1p19q^codel and IDH^mut/1p19q^noncodel) 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 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 IDH^mut/1p19q^noncodel but often accelerated it in IDH^mut/1p19q^codel. 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 IDH^mut/1p19q^codel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs. SIGNIFICANCE: A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Biomarkers, Tumor
Cell Transformation, Neoplastic / genetics*
DNA Copy Number Variations
DNA Mutational Analysis / methods*
Disease Management
Disease Progression
Female
Gene Expression Profiling
Glioma / genetics*
Glioma / mortality
Glioma / pathology*
Glioma / therapy
Humans
Isocitrate Dehydrogenase / genetics*
Male
Middle Aged
Models, Theoretical*
Mutation*
Phenotype
Polymorphism, Single Nucleotide
Prognosis
Treatment Outcome
Tumor Burden

Substances

Biomarkers, Tumor
Isocitrate Dehydrogenase