Identification of Necroptosis-related Molecular Subtypes and
Construction of Necroptosis-related Gene Signature for Glioblastoma
Multiforme

Zhiyong      Li; Yinghui      Jin; Tianshi      Que; Xi-An      Zhang; Guozhong      Yi; Haojie      Zheng; Xi      Yuan; Xiaoyan      Wang; Haiyan      Xu; Jing      Nan; Chao      Chen; Yuankui      Wu; Guanglong      Huang

doi:10.2174/0929867331666230804104329

Abstract

Background: Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies.

Aims: This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM.

Methods: The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs).

Result: Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features.

Conclusion: In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

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[1]
Stoyanov, G.S.; Dzhenkov, D.; Ghenev, P.; Iliev, B.; Enchev, Y.; Tonchev, A.B. Cell biology of glioblastoma multiforme: From basic science to diagnosis and treatment. Med. Oncol.,  2018, 35(3), 27.
 [http://dx.doi.org/10.1007/s12032-018-1083-x] [PMID: 29387965]

[2]
Vitovcova, B.; Skarkova, V.; Rudolf, K.; Rudolf, E. Biology of glioblastoma multiforme—exploration of mitotic catastrophe as a potential treatment modality. Int. J. Mol. Sci.,  2020, 21(15), 5324.
 [http://dx.doi.org/10.3390/ijms21155324] [PMID: 32727112]

[3]
Batash, R.; Asna, N.; Schaffer, P.; Francis, N.; Schaffer, M. Glioblastoma multiforme, diagnosis and treatment; recent literature review. Curr. Med. Chem.,  2017, 24(27), 3002-3009.
 [PMID: 28521700]

[4]
Erthal, L.C.S.; Gobbo, O.L.; Ruiz-Hernandez, E. Biocompatible copolymer formulations to treat glioblastoma multiforme. Acta Biomater.,  2021, 121, 89-102.
 [http://dx.doi.org/10.1016/j.actbio.2020.11.030] [PMID: 33227487]

[5]
Pearson, J.R.D.; Cuzzubbo, S.; McArthur, S.; Durrant, L.G.; Adhikaree, J.; Tinsley, C.J.; Pockley, A.G.; McArdle, S.E.B. Immune escape in glioblastoma multiforme and the adaptation of immunotherapies for treatment. Front. Immunol.,  2020, 11, 582106.
 [http://dx.doi.org/10.3389/fimmu.2020.582106] [PMID: 33178210]

[6]
Carlsson, S.K.; Brothers, S.P.; Wahlestedt, C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol. Med.,  2014, 6(11), 1359-1370.
 [http://dx.doi.org/10.15252/emmm.201302627] [PMID: 25312641]

[7]
Tong, X.; Tang, R.; Xiao, M.; Xu, J.; Wang, W.; Zhang, B.; Liu, J.; Yu, X.; Shi, S. Targeting cell death pathways for cancer therapy: Recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J. Hematol. Oncol.,  2022, 15(1), 174.
 [http://dx.doi.org/10.1186/s13045-022-01392-3] [PMID: 36482419]

[8]
Shan, B.; Pan, H.; Najafov, A.; Yuan, J. Necroptosis in development and diseases. Genes Dev.,  2018, 32(5-6), 327-340.
 [http://dx.doi.org/10.1101/gad.312561.118] [PMID: 29593066]

[9]
Zhang, G.; Wang, J.; Zhao, Z.; Xin, T.; Fan, X.; Shen, Q.; Raheem, A.; Lee, C.R.; Jiang, H.; Ding, J. Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections. Cell Death Dis.,  2022, 13(7), 637.
 [http://dx.doi.org/10.1038/s41419-022-05066-3] [PMID: 35869043]

[10]
Wang, T.; Jin, Y.; Yang, W.; Zhang, L.; Jin, X.; Liu, X.; He, Y.; Li, X. Necroptosis in cancer: An angel or a demon? Tumour Biol.,  2017, 39(6)
 [http://dx.doi.org/10.1177/1010428317711539] [PMID: 28651499]

[11]
Gong, Y.; Fan, Z.; Luo, G.; Yang, C.; Huang, Q.; Fan, K.; Cheng, H.; Jin, K.; Ni, Q.; Yu, X.; Liu, C. The role of necroptosis in cancer biology and therapy. Mol. Cancer,  2019, 18(1), 100.
 [http://dx.doi.org/10.1186/s12943-019-1029-8] [PMID: 31122251]

[12]
Lalaoui, N.; Brumatti, G. Relevance of necroptosis in cancer. Immunol. Cell Biol.,  2017, 95(2), 137-145.
 [http://dx.doi.org/10.1038/icb.2016.120] [PMID: 27922620]

[13]
Ru, B.; Wong, C.N.; Tong, Y.; Zhong, J.Y.; Zhong, S.S.W.; Wu, W.C.; Chu, K.C.; Wong, C.Y.; Lau, C.Y.; Chen, I.; Chan, N.W.; Zhang, J. TISIDB: An integrated repository portal for tumor–immune system interactions. Bioinformatics,  2019, 35(20), 4200-4202.
 [http://dx.doi.org/10.1093/bioinformatics/btz210] [PMID: 30903160]

[14]
Becht, E.; Giraldo, N.A.; Lacroix, L.; Buttard, B.; Elarouci, N.; Petitprez, F.; Selves, J.; Laurent-Puig, P.; Sautès-Fridman, C.; Fridman, W.H.; de Reyniès, A. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol.,  2016, 17(1), 218.
 [http://dx.doi.org/10.1186/s13059-016-1070-5] [PMID: 27765066]

[15]
Geeleher, P.; Cox, N.; Huang, R.S. pRRophetic: An R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One,  2014, 9(9), e107468.
 [http://dx.doi.org/10.1371/journal.pone.0107468] [PMID: 25229481]

[16]
Subramanian, A.; Kuehn, H.; Gould, J.; Tamayo, P.; Mesirov, J.P. GSEA-P : A desktop application for Gene Set Enrichment Analysis. Bioinformatics,  2007, 23(23), 3251-3253.
 [http://dx.doi.org/10.1093/bioinformatics/btm369] [PMID: 17644558]

[17]
Sprooten, J.; De Wijngaert, P.; Vanmeerbeek, I.; Martin, S.; Vangheluwe, P.; Schlenner, S.; Krysko, D.V.; Parys, J.B.; Bultynck, G.; Vandenabeele, P.; Garg, A.D. Necroptosis in immuno-oncology and cancer immunotherapy. Cells,  2020, 9(8), 1823.
 [http://dx.doi.org/10.3390/cells9081823] [PMID: 32752206]

[18]
Nutt, C.L.; Mani, D.R.; Betensky, R.A.; Tamayo, P.; Cairncross, J.G.; Ladd, C.; Pohl, U.; Hartmann, C.; McLaughlin, M.E.; Batchelor, T.T.; Black, P.M.; von Deimling, A.; Pomeroy, S.L.; Golub, T.R.; Louis, D.N. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res.,  2003, 63(7), 1602-1607.
 [PMID: 12670911]

[19]
Aldape, K.; Zadeh, G.; Mansouri, S.; Reifenberger, G.; von Deimling, A. Glioblastoma: Pathology, molecular mechanisms and markers. Acta Neuropathol.,  2015, 129(6), 829-848.
 [http://dx.doi.org/10.1007/s00401-015-1432-1] [PMID: 25943888]

[20]
Verhaak, R.G.W.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; Alexe, G.; Lawrence, M.; O’Kelly, M.; Tamayo, P.; Weir, B.A.; Gabriel, S.; Winckler, W.; Gupta, S.; Jakkula, L.; Feiler, H.S.; Hodgson, J.G.; James, C.D.; Sarkaria, J.N.; Brennan, C.; Kahn, A.; Spellman, P.T.; Wilson, R.K.; Speed, T.P.; Gray, J.W.; Meyerson, M.; Getz, G.; Perou, C.M.; Hayes, D.N. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell,  2010, 17(1), 98-110.
 [http://dx.doi.org/10.1016/j.ccr.2009.12.020] [PMID: 20129251]

[21]
Garofano, L.; Migliozzi, S.; Oh, Y.T.; D’Angelo, F.; Najac, R.D.; Ko, A.; Frangaj, B.; Caruso, F.P.; Yu, K.; Yuan, J.; Zhao, W.; Di Stefano, A.L.; Bielle, F.; Jiang, T.; Sims, P.; Suvà, M.L.; Tang, F.; Su, X.D.; Ceccarelli, M.; Sanson, M.; Lasorella, A.; Iavarone, A. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat. Can.,  2021, 2(2), 141-156.
 [http://dx.doi.org/10.1038/s43018-020-00159-4] [PMID: 33681822]

[22]
Dapash, M.; Hou, D.; Castro, B.; Lee-Chang, C.; Lesniak, M.S. The interplay between glioblastoma and its microenvironment. Cells,  2021, 10(9), 2257.
 [http://dx.doi.org/10.3390/cells10092257] [PMID: 34571905]

[23]
Yan, J.; Wan, P.; Choksi, S.; Liu, Z.G. Necroptosis and tumor progression. Trends Cancer,  2022, 8(1), 21-27.
 [http://dx.doi.org/10.1016/j.trecan.2021.09.003] [PMID: 34627742]

[24]
Aaes, T.L.; Kaczmarek, A.; Delvaeye, T.; De Craene, B.; De Koker, S.; Heyndrickx, L.; Delrue, I.; Taminau, J.; Wiernicki, B.; De Groote, P.; Garg, A.D.; Leybaert, L.; Grooten, J.; Bertrand, M.J.M.; Agostinis, P.; Berx, G.; Declercq, W.; Vandenabeele, P.; Krysko, D.V. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep.,  2016, 15(2), 274-287.
 [http://dx.doi.org/10.1016/j.celrep.2016.03.037] [PMID: 27050509]

[25]
Chen, Z.; Hambardzumyan, D. Immune microenvironment in glioblastoma subtypes. Front. Immunol.,  2018, 9, 1004.
 [http://dx.doi.org/10.3389/fimmu.2018.01004] [PMID: 29867979]

[26]
Yaltirik, C.K.; Yilmaz, S.G.; Ozdogan, S.; Bilgin, E.Y.; Barut, Z.; Ture, U.; Isbir, T. Determination of IDH1, IDH2, MGMT, TERT and ATRX gene mutations in glial tumors. In Vivo,  2022, 36(4), 1694-1702.
 [http://dx.doi.org/10.21873/invivo.12881] [PMID: 35738587]

[27]
Crespo, I.; Vital, A.L.; Gonzalez-Tablas, M.; Patino, M.C.; Otero, A.; Lopes, M.C.; de Oliveira, C.; Domingues, P.; Orfao, A.; Tabernero, M.D. Molecular and genomic alterations in glioblastoma multiforme. Am. J. Pathol.,  2015, 185(7), 1820-1833.
 [http://dx.doi.org/10.1016/j.ajpath.2015.02.023] [PMID: 25976245]

[28]
Koschmann, C.; Lowenstein, P.R.; Castro, M.G. ATRX mutations and glioblastoma: Impaired DNA damage repair, alternative lengthening of telomeres, and genetic instability. Mol. Cell. Oncol.,  2016, 3(3), e1167158.
 [http://dx.doi.org/10.1080/23723556.2016.1167158] [PMID: 27314101]

[29]
Wong, Q.H.W.; Li, K.K.W.; Wang, W.W.; Malta, T.M.; Noushmehr, H.; Grabovska, Y.; Jones, C.; Chan, A.K.Y.; Kwan, J.S.H.; Huang, Q.J.Q.; Wong, G.C.H.; Li, W.C.; Liu, X.Z.; Chen, H.; Chan, D.T.M.; Mao, Y.; Zhang, Z.Y.; Shi, Z.F.; Ng, H.K. Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas. Mod. Pathol.,  2021, 34(7), 1245-1260.
 [http://dx.doi.org/10.1038/s41379-021-00778-x] [PMID: 33692446]

[30]
Yu, W.; Ma, Y.; Hou, W.; Wang, F.; Cheng, W.; Qiu, F.; Wu, P.; Zhang, G. Identification of immune-related lncRNA prognostic signature and mSubtypes for glioblastoma. Front. Immunol.,  2021, 12, 706936.
 [http://dx.doi.org/10.3389/fimmu.2021.706936] [PMID: 34899682]

[31]
Vizcaíno, M.A.; Shah, S.; Eberhart, C.G.; Rodriguez, F.J. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas. Hum. Pathol.,  2015, 46(9), 1323-1330.
 [http://dx.doi.org/10.1016/j.humpath.2015.05.014] [PMID: 26190195]

[32]
Senhaji, N.; Squalli Houssaini, A.; Lamrabet, S.; Louati, S.; Bennis, S. Molecular and circulating biomarkers in patients with glioblastoma. Int. J. Mol. Sci.,  2022, 23(13), 7474.
 [http://dx.doi.org/10.3390/ijms23137474] [PMID: 35806478]

[33]
Yang, Y.; Lv, W.; Xu, S.; Shi, F.; Shan, A.; Wang, J. Molecular and clinical characterization of LIGHT/TNFSF14 expression at tLevel via 998 samples with brain glioma. Front. Mol. Biosci.,  2021, 8, 567327.
 [http://dx.doi.org/10.3389/fmolb.2021.567327] [PMID: 34513918]

[34]
Cao, J.Y.; Guo, Q.; Guan, G.F.; Zhu, C.; Zou, C.Y.; Zhang, L.Y.; Cheng, W.; Wang, G.; Cheng, P.; Wu, A.H.; Li, G.Y. Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma. Aging (Albany NY),  2020, 12(2), 1656-1684.
 [http://dx.doi.org/10.18632/aging.102706] [PMID: 32003759]

[35]
Jahani-Asl, A.; Yin, H.; Soleimani, V.D.; Haque, T.; Luchman, H.A.; Chang, N.C.; Sincennes, M.C.; Puram, S.V.; Scott, A.M.; Lorimer, I.A.J.; Perkins, T.J.; Ligon, K.L.; Weiss, S.; Rudnicki, M.A.; Bonni, A. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat. Neurosci.,  2016, 19(6), 798-806.
 [http://dx.doi.org/10.1038/nn.4295] [PMID: 27110918]

[36]
Oliva, C.R.; Halloran, B.; Hjelmeland, A.B.; Vazquez, A.; Bailey, S.M.; Sarkaria, J.N.; Griguer, C.E. IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling. Cell Commun. Signal.,  2018, 16(1), 61.
 [http://dx.doi.org/10.1186/s12964-018-0273-7] [PMID: 30231881]

[37]
Wang, Y.; Hou, Y.; Zhang, W.; Alvarez, A.A.; Bai, Y.; Hu, B.; Cheng, S.Y.; Yang, K.; Li, Y.; Feng, H. Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response. J. Exp. Clin. Cancer Res.,  2019, 38(1), 147.
 [http://dx.doi.org/10.1186/s13046-019-1151-x] [PMID: 30953555]

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DOI https://dx.doi.org/10.2174/0929867331666230804104329	Print ISSN 0929-8673
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Current Medicinal Chemistry

Identification of Necroptosis-related Molecular Subtypes and Construction of Necroptosis-related Gene Signature for Glioblastoma Multiforme

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