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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Glioma | Research

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma

Authors: Aierpati Maimaiti, Zhaohai Feng, Yanwen Liu, Mirzat Turhon, Zhihao Xie, Yilimire Baihetiyaer, Xixian Wang, Maimaitijiang Kasimu, Lei Jiang, Yongxin Wang, Zengliang Wang, Yinan Pei

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

N7-methylguanosine (m7G) modification signature has recently emerged as a crucial regulator of tumor progression and treatment in cancer. However, there is limited information available on the genomic profile of lower-grade gliomas (LGGs) related to m7G methylation modification genes’ function in tumorigenesis and progression. In this study, we employed bioinformatics methods to characterize m7G modifications in individuals with LGG from The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). We used gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA), CIBERSORT algorithm, ESTIMATE algorithm, and TIDE to evaluate the association between m7G modification patterns, tumor microenvironment (TME) cell infiltration properties, and immune infiltration markers. The m7G scoring scheme using principal component analysis (PCA) was employed to investigate the m7G modification patterns quantitatively. We examined the m7G modification hub genes' expression levels in normal samples, refractory epilepsy samples, and LGG samples using immunohistochemistry, western-blotting, and qRT-PCR. Our findings revealed that individuals with LGG could be categorized into two groups based on m7G scores (high and low) according to the properties of m7G. Moreover, we observed that high m7G score was associated with significant clinical benefit and prolonged survival duration in the anti-PD-1 cohort, while low m7G score was associated with improved prognostic outcomes and increased likelihood of complete or partial response in the anti-PD-L1 cohort. Different m7G subtypes also showed varying Tumor Mutational Burden (TMB) and immune profiles and might have distinct responses to immunotherapy. Furthermore, we identified five potential genetic markers that were highly correlated with the m7G score signature index. These findings provide insight into the features and classification associated with m7G methylation modifications and may aid in improving the clinical outcome of LGG.
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Literature
1.
Louis D, Perry A, Wesseling P, Brat D, Cree I, Figarella-Branger D, Hawkins C, Ng H, Pfister S, Reifenberger G, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–51.PubMedPubMedCentralCrossRef
2.
3.
Gittleman H, Sloan A, Barnholtz-Sloan J. An independently validated survival nomogram for lower-grade glioma. Neuro Oncol. 2020;22(5):665–74.PubMedCrossRef
4.
Liu Z, Ji H, Fu W, Ma S, Zhao H, Wang F, Dong J, Yan X, Zhang J, Wang N, et al. IGFBPs were associated with stemness, inflammation, extracellular matrix remodeling and poor prognosis of low-grade glioma. Front Endocrinol. 2022;13:943300.CrossRef
5.
Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister S, Nishikawa R, Rosenthal M, Wen P, Stupp R, et al. Glioma. Nat Rev Dis Primers. 2015;1:15017.PubMedCrossRef
6.
Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15(7):422–42.PubMedCrossRef
7.
Yan H, Parsons D, Jin G, McLendon R, Rasheed B, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.PubMedPubMedCentralCrossRef
8.
Patel S, Poisson L, Brat D, Zhou Y, Cooper L, Snuderl M, Thomas C, Franceschi A, Griffith B, Flanders A, et al. T2-FLAIR mismatch, an imaging biomarker for IDH and 1p/19q status in lower-grade gliomas: a TCGA/TCIA project. Clin Cancer Res. 2017;23(20):6078–85.PubMedCrossRef
9.
Lai A, Kharbanda S, Pope W, Tran A, Solis O, Peale F, Forrest W, Pujara K, Carrillo J, Pandita A, et al. Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. J Clin Oncol. 2011;29(34):4482–90.PubMedPubMedCentralCrossRef
10.
Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74.PubMedCrossRef
11.
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53.PubMedPubMedCentralCrossRef
12.
Dang L, White D, Gross S, Bennett B, Bittinger M, Driggers E, Fantin V, Jang H, Jin S, Keenan M, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.PubMedPubMedCentralCrossRef
13.
Turcan S, Rohle D, Goenka A, Walsh L, Fang F, Yilmaz E, Campos C, Fabius A, Lu C, Ward P, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479–83.PubMedPubMedCentralCrossRef
14.
Spino M, Kurz S, Chiriboga L, Serrano J, Zeck B, Sen N, Patel S, Shen G, Vasudevaraja V, Tsirigos A, et al. Cell surface notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase-mutant glioma. Clin Cancer Res. 2019;25(4):1261–71.PubMedCrossRef
15.
Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss D, Sahm F, Koelsche C, Wefers A, Reinhardt A, Huang K, et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol. 2018;136(1):153–66.PubMedCrossRef
16.
Bai H, Harmancı A, Erson-Omay E, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay S, Sorensen E, et al. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet. 2016;48(1):59–66.PubMedCrossRef
17.
Johnson B, Mazor T, Hong C, Barnes M, Aihara K, McLean C, Fouse S, Yamamoto S, Ueda H, Tatsuno K, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–93.PubMedCrossRef
18.
Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–43.PubMedCrossRef
19.
Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y, Shimamura T, Niida A, Motomura K, Ohka F, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015;47(5):458–68.PubMedCrossRef
20.
Li G, Wu Z, Gu J, Zhu Y, Zhang T, Wang F, Huang K, Gu C, Xu K, Zhan R, et al. Metabolic signature-based subtypes may pave novel ways for low-grade glioma prognosis and therapy. Front cell Dev Biol. 2021;9:755776.PubMedPubMedCentralCrossRef
21.
22.
Xiang D, Xiao J, Sun S, Fu L, Yao L, Wang G, Liu Z. Differential regulation of DNA methylation at the CRMP2 promoter region between the hippocampus and prefrontal cortex in a CUMS depression model. Front Psych. 2020;11:141.CrossRef
23.
24.
25.
Chen J, Li K, Chen J, Wang X, Ling R, Cheng M, Chen Z, Chen F, He Q, Li S, et al. Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression. Cancer Commun. 2022;42(3):223–44.CrossRef
26.
Orellana E, Liu Q, Yankova E, Pirouz M, De Braekeleer E, Zhang W, Lim J, Aspris D, Sendinc E, Garyfallos D, et al. METTL1-mediated mG modification of Arg-TCT tRNA drives oncogenic transformation. Mol Cell. 2021;81(16):3323-3338.e3314.PubMedPubMedCentralCrossRef
27.
Katsara O, Schneider R. mG tRNA modification reveals new secrets in the translational regulation of cancer development. Mol Cell. 2021;81(16):3243–5.PubMedCrossRef
28.
Gieryng A, Pszczolkowska D, Walentynowicz K, Rajan W, Kaminska B. Immune microenvironment of gliomas. Lab Invest. 2017;97(5):498–518.PubMedCrossRef
29.
Li Z, Zhang H. Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci. 2016;73(2):377–92.PubMedCrossRef
30.
Yang M, Li J, Gu P, Fan X. The application of nanoparticles in cancer immunotherapy: targeting tumor microenvironment. Bioact Mater. 2021;6(7):1973–87.PubMed
31.
Lee H, Chung W, Lee H, Jeong D, Jo A, Lim J, Hong J, Nam D, Jeong B, Park S, et al. Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient. Genome Med. 2020;12(1):47.PubMedPubMedCentralCrossRef
32.
Thorsson V, Gibbs D, Brown S, Wolf D, Bortone D, Ou Yang T, Porta-Pardo E, Gao G, Plaisier C, Eddy J, et al. The immune landscape of cancer. Immunity. 2018;48(4):812-830.e814.PubMedPubMedCentralCrossRef
33.
Ma J, Zhang L, Chen J, Song B, Zang C, Liu H. mGDisAI: N7-methylguanosine (mG) sites and diseases associations inference based on heterogeneous network. BMC Bioinform. 2021;22(1):152.CrossRef
34.
Yang H, Messina-Pacheco J, Corredor A, Gregorieff A, Liu J, Nehme A, Najafabadi H, Riazalhosseini Y, Gao B, Gao Z. An integrated model of acinar to ductal metaplasia-related N7-methyladenosine regulators predicts prognosis and immunotherapy in pancreatic carcinoma based on digital spatial profiling. Front Immunol. 2022;13:961457.PubMedPubMedCentralCrossRef
35.
Cloughesy T, Mochizuki A, Orpilla J, Hugo W, Lee A, Davidson T, Wang A, Ellingson B, Rytlewski J, Sanders C, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–86.PubMedPubMedCentralCrossRef
36.
Schalper K, Rodriguez-Ruiz M, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate M, Inogés S, de Andrea C, de López-Diaz Cerio A, Tejada S, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nature Med. 2019;25(3):470–6.PubMedCrossRef
37.
Hellmann M, Ciuleanu T, Pluzanski A, Lee J, Otterson G, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093–104.PubMedPubMedCentralCrossRef
38.
Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung H, Kindler H, Lopez-Martin J, Miller W, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353–65.PubMedCrossRef
39.
Gao C, Li H, Liu C, Xu X, Zhuang J, Zhou C, Liu L, Feng F, Sun C. Tumor mutation burden and immune invasion characteristics in triple negative breast cancer: genome high-throughput data analysis. Front Immunol. 2021;12:650491.PubMedPubMedCentralCrossRef
40.
Truitt M, Conn C, Shi Z, Pang X, Tokuyasu T, Coady A, Seo Y, Barna M, Ruggero D. Differential requirements for eIF4E dose in normal development and cancer. Cell. 2015;162(1):59–71.PubMedPubMedCentralCrossRef
41.
Ge Y, Zhou F, Chen H, Cui C, Liu D, Li Q, Yang Z, Wu G, Sun S, Gu J, et al. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells. Biochem Biophys Res Commun. 2010;397(4):711–7.PubMedCrossRef
42.
Frosi Y, Lin Y, Shimin J, Ramlan S, Hew K, Engman A, Pillai A, Yeung K, Cheng Y, Cornvik T, et al. Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex. Nat Commun. 2022;13(1):4854.PubMedPubMedCentralCrossRef
43.
Fang D, Peng J, Wang G, Zhou D, Geng X. Upregulation of eukaryotic translation initiation factor 4E associates with a poor prognosis in gallbladder cancer and promotes cell proliferation in vitro and in vivo. Int J Mol Med. 2019;44(4):1325–32.PubMedPubMedCentral
44.
Yang B, Gu A, Wu Y. High EIF4E2 expression is an independent prognostic risk factor for poor overall survival and recurrence-free survival in uveal melanoma. Exp Eye Res. 2021;206:108558.PubMedCrossRef
45.
46.
Melanson G, Timpano S, Uniacke J. The eIF4E2-directed hypoxic cap-dependent translation machinery reveals novel therapeutic potential for cancer treatment. Oxid Med Cell Longev. 2017;2017:6098107.PubMedPubMedCentralCrossRef
47.
Osborne M, Volpon L, Kornblatt J, Culjkovic-Kraljacic B, Baguet A, Borden K. eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition. Proc Natl Acad Sci USA. 2013;110(10):3877–82.PubMedPubMedCentralCrossRef
48.
Landon A, Muniandy P, Shetty A, Lehrmann E, Volpon L, Houng S, Zhang Y, Dai B, Peroutka R, Mazan-Mamczarz K, et al. MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL. Nat Commun. 2014;5:5413.PubMedCrossRef
49.
Gebhardt A, Habjan M, Benda C, Meiler A, Haas D, Hein M, Mann A, Mann M, Habermann B, Pichlmair A. mRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3. Nat Commun. 2015;6:8192.PubMedCrossRef
50.
Pabis M, Neufeld N, Steiner M, Bojic T, Shav-Tal Y, Neugebauer K. The nuclear cap-binding complex interacts with the U4/U6·U5 tri-snRNP and promotes spliceosome assembly in mammalian cells. RNA. 2013;19(8):1054–63.PubMedPubMedCentralCrossRef
51.
Zhang H, Wang A, Tan Y, Wang S, Ma Q, Chen X, He Z. NCBP1 promotes the development of lung adenocarcinoma through up-regulation of CUL4B. J Cell Mol Med. 2019;23(10):6965–77.PubMedPubMedCentralCrossRef
52.
Metadata
Title
N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma
Authors
Aierpati Maimaiti
Zhaohai Feng
Yanwen Liu
Mirzat Turhon
Zhihao Xie
Yilimire Baihetiyaer
Xixian Wang
Maimaitijiang Kasimu
Lei Jiang
Yongxin Wang
Zengliang Wang
Yinan Pei
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01108-4

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