Middle East Journal of Cancer

Positive Expression of IGFBP2 as a Novel Prognostic Biomarker for Patients with Lower-Grade Gliomas

Document Type : Original Article(s)

Authors

Yanguo Li 1
Jiawei Fan 2
Zhuo Shen 3
Jun Zhang 1
Xuemei Yin 1
Fang Han 4
Wenfei Li 1

1 Department of Radiology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China

2 Department of Radiology, Hebei Medical University, Shijiazhuang, Hebei, China

3 Department of Radiology, Tianjin Medical University First Central Clinical College, Tianjin, China

4 Department of Radiology, Affiliated Zhongshan Hospital of DaLian University, Dalian, Liaoning, China

https://doi.org/10.30476/mejc.2024.101125.2014
Abstract
Background: Previous studies have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a target gene associated with the prognosis of various malignant cancers. This study aimed to explore the role and mechanisms of this prognostic signature in patients with low-grade gliomas (LGGs).
Method: A total of 217 patients with LGGs were retrospectively obtained from the Chinese Glioma Genome Atlas as the training group, whereas an additional 190 cases (GSE107850) were collected from the Gene Expression Omnibus as validation data. The Kaplan–Meier method evaluated the overall survival (OS) between the high IGFBP2 and low IGFBP2 expression groups. Univariate and multivariate Cox analyses were used to identify independent prognostic factors associated with survival. Gene set enrichment analysis (GSEA) was conducted to investigate signaling pathways influencing glioma cell proliferation at the transcriptional level of IGFBP2. Statistical analyses and data visualization were performed using R language (version 3.6.3) and Perl software (version 5.38.1), with significance set at P < 0.05.
Results: Kaplan–Meier survival analysis suggested that the group with decreased IGFBP2 expression may have improved OS as compared with the group with high IGFBP2 expression. Increased IGFBP2 expression in gliomas significantly correlated with isocitrate dehydrogenase mutation-wild type. GSEA results revealed that five differential pathways involved in collagen binding, collagen-containing extracellular matrix, collagen metabolic process, collagen trimer, and extracellular structure organization were significantly enriched in patients with glioma with high IGFBP2 expression.
Conclusion: Our study is the first to show that overexpression IGFBP2 could be an independent glioma biomarker. For patients with LGG overexpressing IGFBP2, radiotherapy may be a preferable choice over chemotherapy.

Keywords

IGFBP2
Glioma
Prognosis
Bioinformatics
Genomics
Subjects

How to cite this article:

Li Y, Fan J, Shen Z, Zhang J, Yin X, Han F, et al. Positive expression of IGFBP2 as a novel prognostic biomarker for patients with lower-grade gliomas. Middle East J Cancer. 2025;16(1):79-89. doi: 10.30476/mejc.2024.101125.2014.

  1. Ostrom QT, Gittleman H, Stetson L, Virk S, Barnholtz-Sloan JS. Epidemiology of Intracranial Gliomas. Prog Neurol Surg. 2018;30:1-11. doi: 10.1159/000464374.
  2. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014;16(7):896-913. doi:10.1093/neuonc/nou087. PMID:24842956.PMCID: PMC4057143.
  3. Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18(11):1062-1071. doi: 10.1007/S12094-016-1497-x.
  4. Louis DN, Perry A, Reifenberger G, von Dmling A, Fi Figarella-Branger D, Carenee Wk, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803-20. doi: 10.1007/S00 401-016-1545-1. PMID: 27157931.
  5. Yang W, Warrington NM, Taylor SJ, Whitmire P, Carrasco E, Singleton KW, et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci Transl Med. 2019;11(473):eaao5253. doi: 10.1126/scitranslmed. aa05253. PMID: 30602536.
  6. Lin DD, Deng XY, Zheng DD, Gu CH, Yu LS, Xu SY, et al. The effects of tumor size and postoperative radiotherapy for patients with adult low-grade(WHO grade II)infiltrative supratentorial astrocytoma/oligo­dendroglioma: A population-based and propensity score matched study. Cancer Med. 2018;7(12):5973-87. doi:10.1002/cam4.1853. PMID: 30378290.
  7. Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123-31. doi: 10.1093/neuonc/nox149. PMID: 29016894. PMCID: PMC5761525.
  8. Zhou J, Reddy MV, Wilson BKJ, Blair DA, Taha A, Frampton CM, et al. MR Imaging characteristics associate with tumor-associated macrophages in glioblastoma and provide an improved signature for survival prognostication. AJNR Am J Neuroradiol. 2018;39(2):252-9. doi: 10.3174/ajnr.A5441. PMID: 29191871; PMCID. PMC7410591.
  9. Liu X, Li Y, Qian Z, Sun Z, Xu K, Wang K, et al. A radiomic signature as a non-invasive predictor of progression-free survival in patients with lower-grade gliomas. Neuroimage Clin. 2018;20:1070-7. doi: 10.1016/j.nicl.2018.10.014. PMID: 30366279; PMCID: PMC6202688.
  10. Zhang Y, Li J, Yi K, Feng J, Cong Z, Wang Z, et al. Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma. Proc Natl Acad Sci U S A. 2019;116(14):6975-84. doi: 10.1073/pnas.1814060116. Erratum in: Proc Natl Acad Sci U S A. 2020;117(2):1234. PMID: 30877245; PMCID: PMC6452696.
  11. Zhou Z, Huang R, Chai R, Zhou X, Hu Z, Wang W, et al. Identification of an energy metabolism-related signature associated with clinical prognosis in diffuse glioma. Aging (Albany NY). 2018;10(11):3185-209. doi: 10.18632/aging.101625. PMID: 30407923; PMCID: PMC6286858.
  12. Braman NM, Etesami M, Prasanna P, Dubchuk C, Gilmore H, Tiwari P, et al. Intratumoral and peritumoral radiomics for the pretreatment prediction of pathological complete response to neoadjuvant chemotherapy based on breast DCE-MRI. Breast Cancer Res. 2017;19(1):57. doi: 10.1186/s13058-017-0846-1. Erratum in: Breast Cancer Res. 2017;19(1):80. PMID: 28521821; PMCID: PMC5437672.
  13. Patil SS, Gokulnath P, Bashir M, Shwetha SD, Jaiswal J, Shastry AH, et al. Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis. Neuro Oncol. 2016;18(11):1487-97. doi: 10.1093/ neuonc/now053. PMID: 27044294; PMCID: PMC5063512.
  14. López-Knowles E, Gao Q, Cheang MC, Morden J, Parker J, Martin LA, et al. Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas. Breast Cancer Res. 2016;18(1):39. doi: 10.1186/s13058-016-0696-2. PMID: 27036195; PMCID: PMC4818440.
  15. Russo VC, Azar WJ, Yau SW, Sabin MA, Werther GA. IGFBP-2: The dark horse in metabolism and cancer. Cytokine Growth Factor Rev. 2015;26(3):329-46. doi: 10.1016/j.cytogfr.2014.12.001. PMID: 25544066.
  16. Liu Y, Starr MD, Brady JC, Rushing C, Bulusu A, Pang H, et al. Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus. Mol Cancer Ther. 2015;14(4):1048-56. doi: 10.1158/ 1535-7163.MCT-14-0923-T. PMID: 25695956.
  17. Patil V, Mahalingam K. Comprehensive analysis of reverse phase protein array data reveals characteristic unique proteomic signatures for glioblastoma subtypes. Gene. 2019;685:85-95. doi: 10.1016/j.gene.2018. 10.069. PMID: 30401645.
  18. Bonnal RJP, Yates A, Goto N, Gautier L, Willis S, Fields C, et al. Sharing programming resources between Bio* projects. Methods Mol Biol. 2019;1910:747-66. doi: 10.1007/978-1-4939-9074-0_25. PMID: 312786 84; PMCID: PMC7212028.
  19. Olarerin-George AO, Jaffrey SR. MetaPlotR: a Perl/R pipeline for plotting metagenes of nucleotide modifications and other transcriptomic sites. Bioinformatics. 2017;33(10):1563-4. doi: 10.1093/ bioinformatics/btx002. PMID: 28158328; PMCID: PMC5860047.
  20. Huang LE, Cohen AL, Colman H, Jensen RL, Fults DW, Couldwell WT. IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget. 2017;8(1): 191-202. doi: 10.18632/oncotarget.13329. PMID: 27852048; PMCID: PMC5352106.
  21. Zhang GH, Zhong QY, Gou XX, Fan EX, Shuai Y, Wu MN, et al. Seven genes for the prognostic prediction in patients with glioma. Clin Transl Oncol. 2019;21(10):1327-35. doi: 10.1007/s12094-019-02057-3. PMID: 30762207.
  22. Yuan Q, Cai HQ, Zhong Y, Zhang MJ, Cheng ZJ, Hao JJ, et al. Overexpression of IGFBP2 mRNA predicts poor survival in patients with glioblastoma. Biosci Rep. 2019;39(6):BSR20190045. doi: 10.1042/BSR20 190045. PMID: 31138764; PMCID: PMC6567677.
  23. Luo Q, Zhuang J, Zheng D, Miao C, Luo H, Peng J, et al. IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy. Front Immunol. 2023;14:1282734. doi: 10.3389/fimmu.2023.1282734. PMID: 37928523; PMCID: PMC10620745.
  24. Phillips LM, Zhou X, Cogdell DE, Chua CY, Huisinga A, R Hess K, et al. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies. J Pathol. 2016;239(3):355-64. doi: 10.1002/path.4734. PMID: 27125842; PMCID: PMC4915980.
  25. Lugano R, Vemuri K, Yu D, Bergqvist M, Smits A, Essand M, et al. CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis. J Clin Invest. 2018;128(8):3280-97. doi: 10.1172/JCI97459. PMID: 29763414; PMCID: PMC6063507.
  26. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372(26):2499-508. doi: 10.1056/NEJMoa1407279. PMID: 26061753; PMCID: PMC4489704.
  27. Harland AJ, Perks CM, White P, Kurian KM, Barber HR. Insulin-like growth factor binding protein-2 and glucose-regulated protein 78kDa: Potential biomarkers affect prognosis in IDH-wildtype glioblastoma patients. Cancer Med. 2023;12(13):14426-39. doi: 10.1002/ cam4.6071. PMID: 37212470; PMCID: PMC10358216.
  28. Wesseling P, Capper D. WHO 2016 Classification of gliomas. Neuropathol Appl Neurobiol. 2018;44(2):139-50. doi: 10.1111/nan.12432. PMID: 28815663.
  29. Schiera G, Di Liegro CM, Di Liegro I. Molecular determinants of malignant brain cancers: From intracellular alterations to invasion mediated by extracellular vesicles. Int J Mol Sci. 2017;18(12):2774. doi: 10.3390/ijms18122774. PMID: 29261132; PMCID: PMC5751372.
  30. Deluche E, Bessette B, Durand S, Caire F, Rigau V, Robert S, et al. CHI3L1, NTRK2, 1p/19q and IDH status predicts prognosis in glioma. Cancers (Basel). 2019;11(4):544. doi: 10.3390/cancers11040544. PMID: 30991699; PMCID: PMC6521129.
  31. Duan J, Huang W, Shi H. Positive expression of KIF20A indicates poor prognosis of glioma patients. Onco Targets Ther. 2016;9:6741-9. doi: 10.2147/OTT. S115974. PMID: 27843327; PMCID: PMC5098585.
  32. Marucci G, Morandi L, Magrini E, Farnedi A, Franceschi E, Miglio R, et al. Gene expression profiling in glioblastoma and immunohistochemical evaluation of IGFBP-2 and CDC20. Virchows Arc. 2008;453(6): 599-609.doi:10.1007/s00428-008-0685-7.PMID: 18953566.

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