1. Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas
- Author
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Seishi Ogawa, Tomohide Nishikawa, Masahiro Mizoguchi, Masaki Hirano, Shoichi Deguchi, Fumiharu Ohka, Mitsutoshi Nakada, Yasutomo Momii, Shintaro Yamazaki, Hiroshi Haeno, Ryuta Saito, Yoshihiro Muragaki, Sachi Maeda, Yusuke Okuno, Kuniaki Tanahashi, Junya Yamaguchi, Atsushi Natsume, Yoshitaka Narita, Hiroyuki Shimizu, Melissa Ranjit, Hiromichi Suzuki, Toshihiko Wakabayashi, Yotaro Kitano, Masamichi Takahashi, Kimiyo N. Yamamoto, Jiro Akimoto, Kosuke Aoki, Hideo Nakamura, Tatsuya Abe, Takashi Yamamoto, and Kazuya Motomura
- Subjects
Adult ,Male ,Cancer Research ,DNA Copy Number Variations ,medicine.medical_treatment ,DNA Mutational Analysis ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Malignant transformation ,medicine ,Adjuvant therapy ,Biomarkers, Tumor ,Humans ,PI3K/AKT/mTOR pathway ,Mutation ,Chemotherapy ,business.industry ,Gene Expression Profiling ,Disease Management ,Glioma ,Middle Aged ,Models, Theoretical ,Prognosis ,Isocitrate Dehydrogenase ,Tumor Burden ,Radiation therapy ,Cell Transformation, Neoplastic ,Phenotype ,Treatment Outcome ,Oncology ,Tumor progression ,Cancer research ,Disease Progression ,Female ,business ,Adjuvant - 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 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 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. 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.
- Published
- 2021