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A new method of identifying glioblastoma subtypes and creation of corresponding animal models

Oncogene volume 37, pages 4781–4791 (2018)Cite this article

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Abstract

Glioblastoma (GBM) accounts for up to 50% of brain parenchymal tumors. It is the most malignant type of brain cancer with very poor survival and limited remedies. Cancer subtyping is important for cancer research and therapy. Here, we report a new subtyping method for GBM based on the genetic alterations of CDKN2A and TP53 genes. CDKN2A and TP53 are the most frequently mutated genes with mutation rates of 60 and 30%, respectively. We found that patients with deletion of CDKN2A possess worse survival than those with TP53 mutation. Interestingly, survival of patients with both TP53 mutation and CDKN2A deletion is no worse than for those with only one of these genetic alterations, but similar to those with TP53 mutation alone. Next, we investigated differences in the gene expression profile between TP53 and CDKN2A samples. Consistent with the survival data, the samples with both TP53 mutation and CDKN2A deletion showed a gene expression profile similar to those samples with TP53 mutation alone. Finally, we found that activation of RAS pathway plus Cdkn2a/b silencing can induce GBM, in a similar way to tumor induction by RAS activation plus TP53 silencing. In conclusion, we show that the genetic alterations of CDKN2A and TP53 may be used to stratify GBM, and the new animal models matching this stratification method were generated.

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Acknowledgements

We thank Dr. Dong Yang and Qiu Tu for the useful advice. We also thank Yujie Xia for technical assistance with the histological analysis. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA 01040403), the National Natural Science Foundation of China (NSFC, 81171960), the Top Talents Program of Yunnan Province China (2012HA014) to XZ, and Yunnan Applied Basic Research Projects (2013FA020).

Author contributions:

SA, GL, W-XL, YG, SD, and JZ performed bioinformatic analysis. XZ, ZD, and HY created the mouse glioblastoma model and performed the analysis. JH, IA, and XZ designed the experiments and wrote the manuscript.

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    Authors and Affiliations

    1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, 650223, Kunming, Yunnan, China

      Xia Zhou, Sanqi An, Huihui Yang, Zhi Dai & Xudong Zhao

    2. Kunming College of Life Science, University of Chinese Academy of Sciences, 650204, Kunming, Yunnan, China

      Xia Zhou, Sanqi An, Huihui Yang, Yicheng Guo, Zhi Dai, Shaoxing Dai, Junjuan Zheng, Jingfei Huang & Xudong Zhao

    3. State Key Laboratory of Genetic Resources and Evolution, Laboratory of Evolutionary & Functional Genomics, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China

      Gonghua Li, Sanqi An, Wen-Xing Li, Yicheng Guo, Shaoxing Dai, Junjuan Zheng & Jingfei Huang

    4. Institute of Health Sciences, Anhui University, 230601, Hefei, Anhui, China

      Wen-Xing Li

    5. Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA

      Antonio Iavarone

    6. Kunming Primate Research Center, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China

      Xudong Zhao

    7. KIZ-SU Joint Laboratory of Animal Model and Drug Development, College of Pharmaceutical Sciences, Soochow University, 215000, Suzhou, Jiangsu, China

      Xudong Zhao

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    Zhou, X., Li, G., An, S. et al. A new method of identifying glioblastoma subtypes and creation of corresponding animal models. Oncogene 37, 4781–4791 (2018). https://doi.org/10.1038/s41388-018-0305-1

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