Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas.
Mathematical Modeling and Mutational Analysis Reveal Optimal Therapy to Prevent Malignant Transformation in Grade II IDH-Mutant Gliomas.
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DOI：
10.1158/0008-5472.can-21-0985
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发表时间：
2021-09-15
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影响因子：
11.2
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一个数学模型成功地估计了无恶性转化生存期，并揭示了遗传改变与进展之间的联系，确定了IDH突变型低级别胶质瘤最佳治疗的精确医学方法。异柠檬酸脱氢酶突变型低级别胶质瘤（IDHmut-LGG）生长缓慢，但经常发生恶性转化，最终导致过早死亡。化疗和放疗治疗延长了生存期，但也可以诱导涉及转化的遗传（或表观遗传）改变。在这里，我们基于276个IDHmut-LGG的连续肿瘤体积数据和治疗史开发了肿瘤进展的数学模型，这些IDHmut-LGG通过染色体1 p/19 q共缺失（IDHmut/1 p19 qcodel和IDHmut/1 p19 qnoncodel）进行分类，并进行了全基因组突变分析，包括靶向测序和纵向全外显子组测序数据。这些分析表明，肿瘤突变负荷与恶性转化率呈正相关，化疗和放疗显著抑制了肿瘤生长，但与治疗前相比，每个细胞的恶性转化率增加了1.8至2.8倍。该模型表明，及时的辅助放化疗可以延长小型IDHmut-LGG（≤ 50 cm 3）的无恶性转化生存期。此外，最佳治疗根据大IDHmut-LGG（> 50 cm 3）的遗传改变而不同;辅助治疗延迟了IDHmut/1 p19 qnoncodel的恶性转化，但通常加速了IDHmut/1 p19 qcodel的恶性转化。值得注意的是，PI 3 K突变与恶性转化无关，但增加了术后净增殖率，降低了无恶性转化生存率，提示需要对IDHmut/1 p19 qcodel进行辅助治疗。总的来说，该模型揭示了可以预防恶性转化的治疗策略，从而提高IDHmut-LGG患者的总生存率。一个数学模型成功地估计了无恶性转化生存期，并揭示了遗传改变与进展之间的联系，确定了IDH突变型低级别胶质瘤最佳治疗的精确医学方法。
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. 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. 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.