|
|
Discussion on the classification of glioma based on IDH mutation related metabolic genes |
WU Chenxing1 SONG Hongwang2 FU Xiaojun1 LI Shouwei1 |
1.Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;
2.Department of Emergency, Shengjing Hospital of China Medical University, Liaoning Province, Shenyang 110004, China |
|
|
Abstract Objective To investigate the expression level of metabolic genes associated with isocitrate dehydrogenase (IDH) mutation and the classification of glioma. Methods The transcriptome data of 294 gliomas from the Chinese glioma genome atlas (CGGA) were analyzed by weighted correlation network analysis to screen the differentially expressed genes (DEG) associated with IDH status (IDH mutant type/IDH wild type, IDH-mut/wt). Genes related to metabolic pathways were screened from DEG with reference to KEGG, and cluster typing of IDH-wt gliomas was performed. Survival analysis was used to verify the clinical significance of the new types, and random forest analysis was used to screen the characteristic genes of the new types. Results According to the clustering results, IDH-wt gliomas were divided into C1, C2 and C3 types. The one-year and three-year survival rate analysis showed that IDH-mut and C1 glioma patients had significantly higher survival rate than C2 and C3 patients. Random forest analysis was used to screen out the top five most significant characteristic genes of C1 type, namely TK1, GPX8, RRM2, NNMT and GPX7, and their MDG values were 13.98, 13.94, 10.48, 10.37 and 9.54, respectively. The C1 type was diagnosed by five-gene model. The classification accuracy, sensitivity and specificity of the training group (2/3 of the data from CGGA database were randomly selected) were 95.12%, 93.75% and 95.60%. Conclusion The differentiation of metabolic subtypes of glioma is helpful for predicting prognosis and guiding the individualized treatment of glioma patients.
|
|
|
|
|
[1] Jiang T,Tang GF,Lin Y,et al. Prevalence estimates for primary brain tumors in China:a multi-center cross-sectional study [J]. Chin Med J,2011,124(17):2578-2583.
[2] Waitkus MS,Diplas BH,Yan H. Biological Role and Therapeutic Potential of IDH Mutations in Cancer [J]. Cancer cell,2018,34(2):186-195.
[3] Johnson BE,Mazor T,Hong C,et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma [J]. Science,2014,343(6167):189-193.
[4] Louis DN,Perry A,Reifenberger G,et al. The 2016 World Health Organization Classifcation of Tumors of the Central Nervous System:a summary [J]. Acta Neuropathol,2016, 131(6):803-820.
[5] Parsons DW,Jones S,Zhang X,et al. An integrated genomic analysis of human glioblastoma multiforme [J]. Science,2008,321(5897):1807-1812.
[6] Sun Y,Zhang W,Chen D,et al. A glioma classifcation scheme based on coexpression modules of EGFR and PDGFRA [J]. Proc Natl Acad Sci USA,2014,111(9):3538-3543.
[7] World Medical Association. Declaration of Helsinki:ethical Principles for medical research involving human subjects [J]. JAMA,2013,310(20):2191-2194.
[8] Zhang B,Horvath S. A general framework for weighted gene coexpression network analysis [J]. Stat Appl Genet Mol Biol,2005,4:Article 17.
[9] Hanahan D,Weinberg RA. Hallmarks of cancer:the next generation [J]. Cell,2011,144(5):646-674.
[10] Tateishi K,Wakimoto H,Iafrate AJ. Extreme Vulnerability of IDH Mutant Cancers to NAD+ Depletion [J]. Cancer cell,2015,28(6):773-784.
[11] Pirozzi CJ,Yan H. The implications of IDH mutations for cancer development and therapy [J]. Nat Rev Clin Oncol,2021(Online ahead of print).
[12] Brat DJ,Aldape K,Colman H,et al. cIMPACT-NOW Update 3:Recommended Diagnostic Criteria for “Diffuse Astrocytic Glioma,IDH-wildtype,With Molecular Features of Glioblastoma,WHO Grade Ⅳ” [J]. Acta Neuropathol,2018,136(5):805-810.
[13] Ellison DW,Hawkins C,Jones DTW,et al. IMPACT-NOW update 4:diffuse gliomas characterized by MYB,MYBL1,or FGFR1 alterations or BRAF V600E mutation [J]. Acta Neuropathol,2019,137(4):683-687.
[14] Weller M,van den Bent M,Preusser M,et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood [J]. Nat Rev Clin Oncol,2021,18(3):170-186.
[15] Lokody I. Metabolism:reprogramming metabolic flux in glioma [J]. Nat Rev Cancer,2014,14(11):706-707.
[16] T?觟njes M,Barbus S,Park YJ,et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH [J]. Nat Med,2013,19(7):901-908.
[17] Panosyan EH,Lasky JL,Lin HJ,et al. Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids [J]. J Neurooncol,2016,128(1):57-66.
[18] Bleeker FE,A Atai NA,Lamba S,et al. The prognostic IDH(R132)mutation is associated with reduced NADP(+)-dependent IDH activity in glioblastoma [J]. Acta Neuropathol,2011,119(4):487-494.
[19] Molenaar RJ,Botman D,Smits MA,et al. Radioprotection of IDH-Mutated Cancer Cells by the IDH-Mutant Inhibitor AGI-5198 [J]. Cancer Res,2015,75(22):4790-4802.
[20] Toppo S,Vanin S,Bosello V,et al. Evolutionary and structural insights into the multifaceted glutathione peroxidase(Gpx)superfamil [J]. Antioxid Redox Signal,2008,10(9):1501-1514.
[21] Waitkus MS,Diplas BH,Yan H. Biological Role and Therapeutic Potential of IDH Mutations in Cancer [J]. Cancer Cell,2018,34(2):186-195.
[22] Weiner KX,Ciesla J,Jaffe AB,et al. Chromosomal location and structural organization of the human deoxycytidylate deaminase gene [J]. J Biol Chem,1995,270(32):18727-18729.
[23] Peters GJ,Backus HH,Freemantle S,et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism [J]. Biochim Biophys Acta,2002,1587(2/3):194-205.
[24] Sigmond J,Honeywell RJ,Postma TJ,et al. Gemcitabine uptake in glioblastoma multiforme:potential as a radiosensitizer [J]. Ann Oncol,2009,20(1):182-187.
[25] Hu H,Wang Z,Li M,et al. Gene Expression and Methylation Analyses Suggest DCTD as a Prognostic Factor in Malignant Glioma [J]. Sci Rep,2017,7(1):11568. |
|
|
|