胶质母细胞瘤相关分子标志物研究进展
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摘要
胶质母细胞瘤(glioblastoma,GBM)是中枢神经系统中最常见的原发性恶性肿瘤,肿瘤患者预后差,中位生存时间仅为14个月,并且经过治疗后仍有极高的复发率。现今无法治愈GBM的重要原因之一是人们仍然缺乏对GBM耐药性在肿瘤生物学机制方面的理解。因此,全面探究GBM相关分子标记物对于研究GBM是必不可少的。对近年来研究发现的GBM相关分子标志物进行了全面的介绍,包括表皮生长因子受体(epidermal growth factor receptor, EGFR)、异柠檬酸脱氢酶1/2(isocitrate dehydrogenase 1/2, IDH1/2)、1p19q等以及影像学和免疫学相关分子标志物等,这些分子标志物为胶质母细胞的准确分类和精准治疗提供了理论基础,通过对以上标志物相关的肿瘤分子通路的探究,有利于发展出更为有效的靶向治疗手段,从而大幅提高GBM患者的生存时间。
As one of the common primary malignant tumor in central nerve system, glioblastoma(GBM) demonstrates poor prognosis with 14 months of median survival. Higher recurrence is one of the characters of GBM after treatment. The reason for absence of effective therapy of GBM is our poor understanding of tumor biology and mechanism of GBM. As a consequence, it is necessary that comprehensively understanding molecular markers of GBM to improve clinical outcome. This review introduced GBM markers such as EGFR, IDH1/2 and 1 p19 q as well as imaging biomarkers and immune checkpoints. Accurate classification of GBM and personalized treatment was developed based on these markers. Furthermore, the relevant cancer pathway gives a chance to develop the target treatment and improve the GBM patient survival.
As one of the common primary malignant tumor in central nerve system, glioblastoma(GBM) demonstrates poor prognosis with 14 months of median survival. Higher recurrence is one of the characters of GBM after treatment. The reason for absence of effective therapy of GBM is our poor understanding of tumor biology and mechanism of GBM. As a consequence, it is necessary that comprehensively understanding molecular markers of GBM to improve clinical outcome. This review introduced GBM markers such as EGFR, IDH1/2 and 1 p19 q as well as imaging biomarkers and immune checkpoints. Accurate classification of GBM and personalized treatment was developed based on these markers. Furthermore, the relevant cancer pathway gives a chance to develop the target treatment and improve the GBM patient survival.
引文
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[2] Ostrom Q T, Gittleman H, Stetson L, et al.. Epidemiology of Intracranial Gliomas[M]. Karger Publishers, 2018, 1-11.
[3] Burger P C, Green S B. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme[J]. Cancer, 1987, 59(9): 1617-1625.
[4] Saito T, Sugiyama K, Takeshima Y, et al.. Prognostic implications of the subcellular localization of survivin in glioblastomas treated with radiotherapy plus concomitant and adjuvant temozolomide[J]. J. Neuro., 2018, 128(3): 679-684.
[5] Amatya V J, Naumann U, Weller M, et al.. TP53 promoter methylation in human gliomas[J]. Acta Neuropathol., 2005, 110(2): 178-184.
[6] Baeza N, Weller M, Yonekawa Y, et al.. PTEN methylation and expression in glioblastomas[J]. Acta Neuropathol., 2003, 106(5): 479-485.
[7] Karsy M, Neil J A, Guan J, et al.. A practical review of prognostic correlations of molecular biomarkers in glioblastoma[J]. Neuro. Focus, 2015, 38(3): E4.
[8] Hegi M E, Diserens A C, Gorlia T, et al.. MGMT gene silencing and benefit from temozolomide in glioblastoma[J]. New England J. Med., 2005, 352(10): 997-1003.
[9] Gorlia T, van den Bent M J, Hegi M E, et al.. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: Prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE. 3[J]. Lancet Oncol., 2008, 9(1): 29-38.
[10] Weller M, Tabatabai G, K?stner B, et al.. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: The DIRECTOR trial[J]. Clin. Cancer Res., 2015,21(9):2057-2064.
[11] Zarnett O J, Sahgal A, Gosio J, et al.. Treatment of elderly patients with glioblastoma: A systematic evidence-based analysis[J]. JAMA Neurol., 2015, 72(5): 589-596.
[12] Wick W, Meisner C, Hentschel B, et al.. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation[J]. Neurology, 2013, 81(17): 1515-1522.
[13] Herbst R S. Review of epidermal growth factor receptor biology[J]. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(2): S21-S26.
[14] Bush N A O, Butowski N. The effect of molecular diagnostics on the treatment of glioma[J]. Curr. Oncol. Rep., 2017, 19(4): 26-35.
[15] Reardon D A, Wen P Y, Mellinghoff I K. Targeted molecular therapies against epidermal growth factor receptor: Past experiences and challenges[J]. Neuro. Oncol., 2014, 16(8): 7-13.
[16] Westphal M, Maire C L, Lamszus K. EGFR as a target for glioblastoma treatment: An unfulfilled promise[J]. CNS Drugs, 2017, 31(9): 723-735.
[17] Downward J, Yarden Y, Mayes E, et al.. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences[J]. Nature, 1984, 307(5951): 521-527.
[18] Stancheva G, Goranova T, Laleva M, et al.. IDH1/IDH2 but not TP53 mutations predict prognosis in Bulgarian glioblastoma patients[J]. Biol. Med. Res. Int., 2014, doi: 10.1155/2014/654727.
[19] Yan H, Parsons D W, Jin G, et al.. IDH1 and IDH2 mutations in gliomas[J]. New England J. Med., 2009, 360(8): 765-773.
[20] Dang L, Yen K, Attar E C. IDH mutations in cancer and progress toward development of targeted therapeutics[J]. Ann. Oncol., 2016, 27(4): 599-608.
[21] Leu S, von Felten S, Frank S, et al.. IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival[J]. Neuro. Oncol., 2013, 15(4): 469-479.
[22] Beiko J, Suki D, Hess K R, et al.. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection[J]. Neuro. Oncol., 2013, 16(1): 81-91.
[23] Dang L, Yen K, Attar E C. IDH mutations in cancer and progress toward development of targeted therapeutics[J]. Ann. Oncol., 2016, 27(4): 599-608.
[24] Louis D N, Holland E C, Cairncross J G. Glioma classification: A molecular reappraisal[J]. Am. J. Pathol., 2001, 159(3): 779-786.
[25] Riemenschneider M J, Jeuken J W M, Wesseling P, et al.. Molecular diagnostics of gliomas: State of the art[J]. Acta Neuropathol., 2010, 120(5): 567-584.
[26] Smith J S, Perry A, Borell T J, et al.. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas[J]. J. Clin. Oncol., 2000, 18(3): 636-636.
[27] Boots-Sprenger S H E, Sijben A, Rijntjes J, et al.. Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: Use with caution[J]. Modern Pathol., 2013, 26(7): 922.
[28] Zhao J, Ma W, Zhao H. Loss of heterozygosity 1p/19q and survival in glioma: A meta-analysis[J]. Neuro. Oncol., 2013, 16(1): 103-112.
[29] Nandakumar P, Mansouri A, Das S. The role of ATRX in glioma biology[J]. Front. Oncol., 2017, 7: 236.
[30] Wiestler B, Capper D, Holland-Letz T, et al.. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis[J]. Acta Neuropathol., 2013, 126(3): 443-451.
[31] Koschmann C, Calinescu A A, Nunez F J, et al.. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma[J]. Sci. Transl. Med., 2016, 8(328): 32828-32828.
[32] Killela P J, Reitman Z J, Jiao Y, et al.. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal[J]. Proc. Natl. Acad. Sci. USA, 2013, 110(15): 6021-6026.
[33] Simon M, Hosen I, Gousias K, et al.. TERT promoter mutations: A novel independent prognostic factor in primary glioblastomas[J]. Neuro. Oncol., 2014, 17(1): 45-52.
[34] Labussière M, Boisselier B, Mokhtari K, et al.. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes[J]. Neurology, 2014, 83(13): 1200-1206.
[35] Eckel-Passow J E, Lachance D H, Molinaro A M, et al.. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors[J]. New England J. Med., 2015, 372(26): 2499-2508.
[36] Shankar G M, Francis J M, Rinne M L, et al.. Rapid intraoperative molecular characterization of glioma[J]. JAMA Oncol., 2015, 1(5): 662-667.
[37] Henriksen M, Johnsen K B, Olesen P, et al.. MicroRNA expression signatures and their correlation with clinicopathological features in glioblastoma multiforme[J]. Neuromol. Med., 2014, 16(3): 565-577.
[38] Kim T M, Huang W, Park R, et al.. A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs[J]. Cancer Res., 2011, 71(9):3387-3399..
[39] Li Y, Min W, Li M, et al.. Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis[J]. Int. J. Mol. Med., 2016, 38(4): 1170-1178.
[40] Rao S A M, Santosh V, Somasundaram K. Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma[J]. Modern Pathol., 2010, 23(10): 1404.
[41] Srinivasan S, Patric I R P, Somasundaram K. A ten-microRNA expression signature predicts survival in glioblastoma[J]. PLoS ONE, 2011, 6(3): e17438.
[42] Guan Y, Mizoguchi M, Yoshimoto K, et al.. MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance[J]. Clin. Cancer Res., 2010, 16(16):4289-4297.
[43] Lakomy R, Sana J, Hankeova S, et al.. MiR-195, miR-196b, miR-181c, miR-21 expression levels and O6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients[J]. Cancer Sci., 2011, 102(12): 2186-2190.
[44] Haemmig S, Baumgartner U, Glück A, et al.. miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas[J]. Cell Death Disease, 2014, 5(6): e1279.
[45] Zhang W, Zhang J, Yan W, et al.. Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme[J]. Cancer, 2013, 119(4): 814-824.
[46] Hayes J, Thygesen H, Tumilson C, et al.. Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature[J]. Mol. Oncol., 2015, 9(3): 704-714.
[47] Liebelt B D, Shingu T, Zhou X, et al.. Glioma stem cells: Signaling, microenvironment, and therapy[J]. Stem Cells Int., 2016, doi: 10.1155/2016/7849890.
[48] Bloch O, Crane C A, Kaur R, et al.. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages[J]. Clin. Cancer Res., 2013, 19(12):3165-3175.
[49] Doucette T, Rao G, Rao A, et al.. Immune heterogeneity of glioblastoma subtypes: Extrapolation from the cancer genome atlas[J]. Cancer Immunol. Res., 2013, 1(2):112-122..
[50] Simonelli M, Persico P, Perrino M, et al.. Checkpoint inhibitors as treatment for malignant gliomas:“A long way to the top”[J]. Cancer Treat. Rev., 2018, doi:10.1016/j.ctrv.2018.06.016.
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