|Year : 2016 | Volume
| Issue : 4 | Page : 125-129
The progress in molecular biomarkers of gliomas
Jing Qi1, Hongwei Yang2, Xin Wang2, Yanyang Tu1
1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
|Date of Submission||26-Jul-2016|
|Date of Acceptance||17-Aug-2016|
|Date of Web Publication||26-Aug-2016|
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, Shaanxi
Source of Support: None, Conflict of Interest: None
Malignant glioma, a common form of central nervous system tumor, has a poor prognosis. The overall survival of these patients is as low as 12–14 months only. In general, the progress in personal precision medication has been gradually directed toward the molecular profiling of the tumors. Malignant glioma is one such tumor in which treatment response relies largely on its molecular characteristics, thus making the understanding of these markers essential to deliver the best treatment possible. Representative molecular markers (isocitrate dehydrogenase 1 mutation, 1p19q codeletion, epidermal growth factor receptor variant III amplification, human telomerase reverse transcriptase promoter mutations, alpha thalassemia/mental retardation syndrome X-linked mutation, and O-methylguanine DNA methyltransferase promoter methylation) are described/discussed in this article. Furthermore, the research prospects of cell-free DNA, regarded as a new developing trend of molecular markers, are discussed. There is an immense hope in these promising molecular markers which are expected to improve the overall survival and quality of life of malignant glioma patients.
Keywords: Glioblastoma, molecular markers, therapeutic strategies
|How to cite this article:|
Qi J, Yang H, Wang X, Tu Y. The progress in molecular biomarkers of gliomas. Cancer Transl Med 2016;2:125-9
| Introduction|| |
With its incidence rate almost accounting for 50%, glioma is the most common form of primary central nervous system tumors. The overall survival, after diagnosis, of glioma patients is as low as 12–14 months. Based on the involved cell types, gliomas are classified as oligodendroglioma, astrocytoma, ependymoma, medulloblastoma, and mixed glioma. The highly invasive character of gliomas, without obvious boundaries with respect to normal tissue around the tumor, makes its complete surgical resection hard to accomplish. Thus, specialists recommend a combination therapy, including surgery, chemotherapy, and radiation therapy, to delay the recurrence and prolong survival.,,, Chemotherapy and radiation therapy target the cells in their growth phase but fail to affect the quiescent glioma stem cell. This is why invasive glioma has a low cure rate and a high recurrence rate, despite the combination therapy. However, recently, immunotherapy has shown promise in treating such devastating disease. A deeper understanding of the specific molecular markers is the core part of such immunotherapy, which we have attempted to discuss here.
| Isocitrate Dehydrogenase Encoding Gene Mutation|| |
Isocitrate dehydrogenase (IDH), one of the key factors in metabolism, encodes IDH that catalyzes the oxidative decarboxylation process, producing α-ketoglutarate and CO2. Its two variants, IDH1 and IDH2, use NADP + as a cofactor to catalyze the reaction. IDH mutations exist in more than 70% of low-grade and malignant gliomas.,, The most common mutation is seen in IDH1 variant (over 95%) which occurs at R132H, which is a single amino acid residue of the IDH1 active site. This results in a loss of the enzyme's ability to catalyze the conversion of isocitrate to α-ketoglutarate, and instead the IDH1 mutant results in catalyzing α-ketoglutarate to 2-hydroxy glutaric acid, which is associated with hereditary hypertension, cancer, metabolic genetic instability, and malignant transformation. Since IDH1 mutation is the most common and earliest genetic changes in glioma, it serves as an early biomarker in diagnosis and prognosis of glioma patients. Li et al. found that glioma patients with IDH1 mutations had higher level of pyruvate carboxylase than glioma patients without IDH1 mutations. Esmaeili et al. showed that IDH1-R132H mutations affect ethanolamine phosphate and glycerol phosphate, choline, and phospholipid metabolism in glioma.
Forced expression of IDH1 mutation in astrocytes stimulates methylation in G-CIMP-positive low-grade gliomas. Duncan et al. found that IDH1 mutation is the molecular basis of G-CIMP phenotype, which emphasizes the importance of carcinogenesis and aid in the development of epigenetics-based treatment strategies. Schumacher et al. found that CD4+ Th1 cells and antibodies occur spontaneously in IDH1-R132H glioma patients and a vaccine targeting IDH1-R132H exhibit potent mutation-specific antitumor immune response.
IDH mutations had been associated to glioma prognosis,,, with the IDH1/2-mutated patients exhibiting favorable prognosis and longer survival duration.,, Further, the IDH mutations are negatively correlated to the tumor grade; IDH mutation rates of Class II, III, and IV level glioma were 77%, 55%, and 6% respectively. The mutations are also positively correlated with therapeutic response of the patient.
| 1p19qcodeletion|| |
1p19q codeletion occurs at the long arm of chromosome 19 (19q) and the short arm of chromosome 1 (1p) in gliomas. Allelic loss in 1p has been found in gliomas with a major oligodendroglial component; grade II oligodendrogliomas, grade III anaplastic oligodendrogliomas, and grade II to III mixed oligoastrocytomas. The incidence of allelic loss in 19q is particularly high in oligodendroglial tumors (81%) and mixed gliomas (31%). More than 75% of tumors with allelic deletion in 19q also exhibited a loss of heterozygosity in loci in 1p. Chemotherapy of the 25 glioma patients with temozolomide (TMZ) found that the response rate of patients with 1p19q codeletion was better than patients without the same. After treating with TMZ, the growth rate of tumor (in diameter) in patients with 1p19q codeletion was smaller than the other patients. The patients with 1p19q codeletion showed more relapse or less relapse after TMZ therapy. It is shown that 1p19q codeletion may delay the development of resistance to TMZ.,
Currently, the 1p19q codeletion, in combination with other markers, is used to evaluate the prognosis and treatment response of glioma patients. 1p19q codeletion and O -methylguanine DNA methyltransferase (MGMT) promoter methylation are independent positive prognostic markers. Furthermore, 1p19q deletion also exhibits IDH mutations. Combined IDH mutation, MGMT promoter methylation, and 1p19q codeletion greatly increased patient survival rates.,
In addition, 1p19q codeletion is an important indicator of the prognosis and chemosensitivity of low-grade gliomas. Among the oligodendroglioma and grade II glioblastoma patients, 5-year survival rates of patients with 1p19q codeletion were significantly higher than patients without the same.,
| Epidermal Growth Factor Receptor Variant Iii Amplification|| |
Epidermal growth factor belongs to receptor tyrosine kinase (RTK) family, a membrane receptor superfamily, with intrinsic protein tyrosine kinase activity. In glioblastoma, a relatively specific mutation of epidermal growth factor (EGFR), called EGFR variant III (EGFRvIII), is often observed. Mutations, amplifications, or misregulations of EGFR family members are involved in about 30% of all epithelial cancers. Constitutively active mutant EGFRvIII is present in 25–30% of malignant glioma patients with EGFR amplification/overexpression., EGFRvIII gene subtypes were identified in 12 of 22 samples and were accompanied by a lack of p53 mutation. A study also found that the expression of G-CIMP phenotype led to the repression of EGFR signaling.
EGFRvIII plays a role in tumorigenesis by activating other RTK. Greenall et al. demonstrated that EGFRvIII activity in U87MG glioma cells is directly proportional to the MET transactivation. The simultaneous targeting of both EGFRvIII and transactivated RTKs, resulted in significantly better survival of the test subjects in a mouse model, indicating that blocking both transactivated RTK and EGFRvIII may be an effective treatment strategy for EGFRvIII-positive glioma condition.
O-Methylguanine Dna Methyltransferase Promoter Hypermethylation
MGMT is a ubiquitous DNA repair enzyme which plays an important role in resisting cellular DNA damage induced by alkylating agents (e.g. TMZ), by directly removing the alkyl group from the O -atom of guanine. This process does not require other cofactors, as the MGMT protein acts as a methyltransferase and methyl acceptor for MGMT inactivation during methylation. Clinical trials have proved that MGMT promoter methylation is a positive prognostic marker that renders tumors more sensitive to radiation therapy. Substantial evidence also shows that MGMT methylation level is a positive predictive marker for the responsiveness of newly diagnosed glioma to alkylating agents.,, Further, two prospective randomized phase III clinical trials reported that MGMT promoter methylation status plays a predictive role in elderly patients who receive TMZ treatment., The TMZ chemotherapeutic sensitivity of glioma patients with MGMT promoter methylation was found to be higher than those without MGMT promoter methylation, and thus it was reported as a sign for higher TMZ chemotherapeutic sensitivity and better prognosis.
| Human Telomerase Reverse Transcriptase Promoter Mutations|| |
Human telomerase maintains the telomere length at the ends of chromosomes maintaining the cells ability of active division. Human telomerase is a ribonucleoprotein enzyme consisting of human telomerase reverse transcriptase (hTERT), human telomerase RNA component, and human telomerase-associated protein 1, where hTERT is the catalytic subunit of telomerase. A variation in the telomere maintenance is seen in most of the tumors. TERT promoter mutation occurs mainly in 124 and 146 bp upstream of the transcription start site. These mutations will enhance TERT promoter activity. One study showed that the mutations in TERT promoter will enhance the expression levels of telomerase and its activity. After the tumor genetic analysis, the researchers found that about 70–80% of primary glioblastoma and 70% of oligodendroglioma had TERT promoter mutations. The hTERT promoter mutation finding is of concern as it is an early finding in progressive glioblastoma.,
Findings from the brain tumor study indicate that glioblastoma patients with TERT promoter mutations has shorter overall survival rates  and exhibited a negative correlation with degree of glioma malignancy. TERT promoter mutations also showed a negative correlation with IDH1 and TP53 mutation while it was positively correlated with EGFR amplification. These mutations are useful in predicting the life span and prognosis of glioma patients; the median survival time of Grade III–IV glioma patients with IDH mutation, TERT mutation, or IDH + TERT mutation had a median survival time of 57, 11.5, or 125 months, respectively.
| Alpha Thalassemia/Mental Retardation Syndrome X-Linked Gene Mutation|| |
The proteins encoded by alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene are chromatin remodeling proteins, which form stable protein complexes with DAXX (death-domain associated protein) to interplay with histone H3.3 assembling chromatin and telomeres. ATRX mutations results in telomere maintenance through telomere-independent pathway, leading to indefinite dividing of cells.
The difference between ARTX and TERT promoter mutation is that the ARTX mutation is associated with no telomerase activity, whereas TERT promoter mutation is associated with enhanced telomerase activity. ATRX mutations in gliomas occur mainly in the Grade II–III astrocytomas, oligodendroglioma, and secondary glioblastomas, whereas TERT promoter mutation is seen mainly in primary glioblastoma and oligodendroglioma. Moreover, the presence of both IDH and ATRX mutations in glioma can be considered as the pathological diagnosis of astrocytoma.,
| Other Markers|| |
There are few other markers related to the prognosis of patients with glioma. NF1 mutations frequently occur in mesenchymal subtypes. Ozawa et al. found that NF1 deletions may render neuronal precursor tumors into mesenchymal subtypes. Increased expression of Myc is seen in 60–80% of gliomas and its expression level has been associated with the grading of the condition. Increased activity of the Myc gene plays an important role in neuronal differentiation of glioblastoma initiation cells, in addition to promoting their self-renewal ability.,
Further, in diffuse intrinsic pontine gliomas, recurrent somatic mutations of the activin receptor gene, ACVR1, were identified by combining whole-genome, whole-exome, methylome sequencing, and transcriptome. These mutations result in constitutively activated proteins, which lead to the phosphorylation of SMAD and the overexpression of its downstream targets, inhibitor of DNA binding protein 1 and 2 (ID1/2). In pediatric midline high-grade astrocytomas, a gain-of-function mutation in ACVR1 leads to the hyperactivation of bone morphogenetic protein (BMP)-ACVR1 pathway, resulting in increased phosphorylation of SMAD 1/5/8, and the activation of BMP target genes. In brain-stem gliomas, tumor-specific mutations in PPM1D were identified by targeted mutational analysis and exome sequencing. Being the high-frequency target of somatic mutation, PPM1D mutations enhance the cell's capacity to inhibit the activation of DNA damage response, making it a potential target in brain stem glioma treatment.
| Conclusion|| |
Identifying the molecular characteristics of the glioma regulation network may increase the precision of personalized medication. The integrity of circulating cell-free (cfDNA) in serum or plasma appears to be of diagnostic and prognostic value in cancer. During apoptosis and necrosis of cancer cells, cfDNA is released into the tumor microenvironment. The size of 70–200 bp cfDNA fragment ranges from small to the large fragment of approximately 21 kb. The half-life of cfDNA varies from 5 min to several hours, as these fragments are quickly and effectively cleared in liver and kidney. Thus, cfDNAs are perfect targets for biopsies as they reflect disease progression and turnover in real time.,,
There is no single molecular marker that can reveal the condition of all gliomas. Future studies on glioma biomarkers must focus on the identification of specific associated molecules while improving the sensitivity of their detection along with the feasibility of the procedure. To better understand biological characteristics of glioma tumor, comprehensive analysis of the associated multiple molecular markers should be performed. However, biopsy has not timely reacted the state of the tumor due to the existence of heterogeneity. Despite all the advances, accurate and comprehensive diagnosis of glioma is still not feasible, thus keeping the challenge open for future studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
de Groot JF. High-grade gliomas. Continuum (Minneap Minn)
2015; 21: 332–44.
Wu CX, Lin GS, Lin ZX, Zhang JD, Liu SY, Zhou CF. Peritumoral edema shown by MRI predicts poor clinical outcome in glioblastoma. World J Surg Oncol
2015; 13: 97.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med
2005; 352 (10): 987–96.
Bell C, Dowson N, Fay M, Thomas P, Puttick S, Gal Y, Rose S. Hypoxia imaging in gliomas with F-fluo-romisonidazole PET: toward clinical translation. Semin Nucl Med
2015; 45 (2): 136–50.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature
2012; 483 (7390): 479–83.
Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, Viale A, Riggins GJ, Chan TA. Efficient induction of differenti-ation and growth inhibition in IDH1 mutant glioma cells by the DNMT in-hibitor decitabine. Oncotarget
2013; 4 (10): 1729–36.
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol
2008; 116 (6): 597–602.
Izquierdo-Garcia JL, Cai LM, Chaumeil MM, Eriksson P, Robinson AE, Pieper RO, Phillips JJ, Ronen SM. Glioma cells with the IDH1 mutation modulate metabolic fractional flux through pyruvate carbox-ylase. PLoS One
2014; 9 (9): e108289.
Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, Selfridge J, Zurayk M, Lou JJ, Everson RG, Wu KC, Faull KF, Cloughesy T, Liau LM, Lai A. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol
2013; 15 (1): 57–68.
Esmaeili M, Hamans BC, Navis AC, van Horssen R, Bathen TF, Gribbestad IS, Leenders WP, Heerschap A. IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma. Cancer Res
2014; 74 (17): 4898–907.
Duncan CG, Barwick BG, Jin G, Rago C, Kapoor-Vazirani P, Powell DR, Chi JT, Bigner DD, Vertino PM, Yan H. A heterozygous IDH1R132H/WT mu-tation induces genome-wide alterations in DNA methylation. Genome Res
2012; 22 (12): 2339–55.
Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balß J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmüller SB, Okun J, Stevanović S, Riemer AB, Sahin U, Friese MA, Beckhove P, von Deimling A, Wick W, Platten M. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature
2014; 512 (7514): 324–7.
Killela PJ, Pirozzi CJ, Healy P, Reitman ZJ, Lipp E, Rasheed BA, Yang R, Diplas BH, Wang Z, Greer PK, Zhu H, Wang CY, Carpenter AB, Friedman H, Friedman AH, Keir ST, He J, He Y, McLendon RE, Herndon JE 2nd
, Yan H, Bigner DD. Mutations in, IDH1, IDH2, and in the, TERT, promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget
2014; 5 (6): 1515–25.
Gorovets D, Kannan K, Shen R, Kastenhuber ER, Islamdoust N, Campos C, Pentsova E, Heguy A, Jhanwar SC, Mellinghoff IK, Chan TA, Huse JT. IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res
2012; 18 (9): 2490–501.
Lee KS, Choe G, Nam KH, Seo AN, Yun S, Kim KJ, Cho HJ, Park SH. Immunohistochemical classification of primary and secondary glioblastomas. Korean J Pathol
2013; 47 (6): 541–8.
Mukasa A, Takayanagi S, Saito K, Shibahara J, Tabei Y, Furuya K, Ide T, Narita Y, Nishikawa R, Ueki K, Saito N. Significance of IDH, mutations varies with tumor histology, grade, and genetics in Japanese glioma patients. Cancer Sci
2012; 103 (3): 587–92.
Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, Paris S, Boisselier B, Idbaih A, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology
2010; 75 (17): 1560–6.
Sabha N, Knobbe CB, Maganti M, Al Omar S, Bernstein M, Cairns R, Çako B, von Deimling A, Capper D, Mak TW, Kiehl TR, Carvalho P, Garrett E, Perry A, Zadeh G, Guha A, Croul S. Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas. Neuro Oncol
2014; 16 (7): 914–23.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med
2009; 360 (8): 765–73.
Bello MJ, Vaquero J, de Campos JM, Kusak ME, Sarasa JL, Saez-Castresana J, Pestana A, Rey JA. Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors. Int J Cancer
1994; 57 (2): 172–5.
Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol
1994; 145 (5): 1175–90.
Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol
2009; 27 (35): 5874–80.
Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol
2013; 31 (3): 337–43.
Zhang ZY, Chan AK, Ng HK, Ding XJ, Li YX, Shi ZF, Zhu W, Zhong P, Wang Y, Mao Y, Yao Y, Zhou LF. Surgically treated incidentally discovered low-grade gliomas are mostly IDH mutated and 1p19q co-deleted with favorable prognosis. Int J Clin Exp Pathol
2014; 7 (12): 8627–36.
Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay JL, Mariani L. IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol
2013; 15 (4): 469–79.
van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer ph. J Clin Oncol
2006; 24 (18): 2715–22.
Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG, Buckner JC. A t (1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res
2006; 66 (20): 9852–61.
Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG 2nd
, Buckner JC, James CD, Aldape K. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol
2007; 25 (16): 2288–94.
Cominelli M, Grisanti S, Mazzoleni S, Branca C, Buttolo L, Furlan D, Liserre B, Bonetti MF, Medicina D, Pellegrini V, Buglione M, Liserre R, Pellegatta S, Finocchiaro G, Dalerba P, Facchetti F, Pizzi M, Galli R, Poliani PL. EGFR amplified and over-expressing glioblastomas and association with better response to adjuvant metronomic temozolomide. J Natl Cancer Inst
2015; 107 (5): djv041.
Li J, Taich ZJ, Goyal A, Gonda D, Akers J, Adhikari B, Patel K, Vandenberg S, Yan W, Bao Z, Carter BS, Wang R, Mao Y, Jiang T, Chen CC. Epigenetic suppression of EGFR signaling in G-CIMPþ glioblastomas. Oncotarget
2014; 5 (17): 7342–56.
Greenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budiman S, Devlin M, Street I, Adams TE, Johns TG. EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and ther-apeutic implications. Oncogene
2015; 34 (41): 5277–87.
Zhu Z, Du S, Ding F, Guo S, Ying G, Yan Z. Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O (6)-methylguanine-DNA methyltransferase (MGMT) expression. Am J Transl Res
2016; 8 (7): 3299–308.
Berghoff AS, Hainfellner JA, Marosi C, Preusser M. Assessing MGMT methylation status and its current impact on treatment in glioblastoma. CNS Oncol
2015; 4 (1): 47–52.
Mur P, Rodríguez de Lope Á, Díaz-Crespo FJ, Hernández-Iglesias T, Ribalta T, Fiaño C, García JF, Rey JA, Mollejo M, Meléndez B. Impact on prognosis of the regional distribution of MGMT methylation with respect to the CpG island methylator phenotype and age in glioma patients. J Neurooncol
2015; 122 (3): 441–50.
Minniti G, Salvati M, Arcella A, Buttarelli F, D'Elia A, Lanzetta G, Esposito V, Scarpino S, Maurizi Enrici R, Giangaspero F. Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol
2011; 102 (2): 311–6.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med
2005; 352 (10): 997–1003.
Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol
2012; 13 (9): 916–26.
Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 tria. Lancet Oncol
2012; 13 (7): 707–15.
Spiegl-Kreinecker S, Lötsch D, Ghanim B, Pirker C, Mohr T, Laaber M, Weis S, Olschowski A, Webersinke G, Pichler J, Berger W. Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis. Neuro Oncol
2015; 17 (9): 1231–40.
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet
2001; 10 (7): 687–92.
Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, Chada AR, Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, Zheng S, Reis GF, Pico AR, O'Neill BP, Buckner JC, Giannini C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados MD, Wiemels J, Wiencke JK, Wrensch MR, Jenkins RB. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med
2015; 372 (26): 2499–508.
Tabori U, Ma J, Carter M, Zielenska M, Rutka J, Bouffet E, Bartels U, Malkin D, Hawkins C. Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J Clin Oncol
2006; 24 (10): 1522–8.
Simon M, Hosen I, Gousias K, Rachakonda S, Heidenreich B, Gessi M, Schramm J, Hemminki K, Waha A, Kumar R. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro Oncol
2014; 17 (1): 45–52.
Abedalthagafi M, Phillips JJ, Kim GE, Mueller S, Haas-Kogen DA, Marshall RE, Croul SE, Santi MR, Cheng J, Zhou S, Sullivan LM, Martinez-Lage M, Judkins AR, Perry A. The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas. Mod Pathol
2013; 26 (11): 1425–32.
Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr., Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IeM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A
2013; 110 (15): 6021–6.
Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK, Bettegowda C, Agrawal N, Lipp E, Pirozzi C, Lopez G, He Y, Friedman H, Friedman AH, Riggins GJ, Holdhoff M, Burger P, McLendon R, Bigner DD, Vogelstein B, Meeker AK, Kinzler KW, Papadopoulos N, Diaz LA, Yan H. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget
2012; 3 (7): 709–22.
Ozawa T, Riester M, Cheng YK, Huse JT, Squatrito M, Helmy K, Charles N, Michor F, Holland EC. Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell
Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E, Cuartas I, Redondo-Campos S, Folch G, Gonzàlez-Juncà A, Sodir NM, Massó-Vallés D, Beaulieu ME, Swigart LB, Mc Gee MM, Somma MP, Nasi S, Seoane J, Evan GI, Soucek L. Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat Commun
2014; 5: 4632.
Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, dePinho RA. Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol
2008; 73: 427–37.
Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Onar-Thomas A, Huether R, Kriwacki R, Parker M, Gupta P, Becksfort J, Wei L, Mulder HL, Boggs K, Vadodaria B, Yergeau D, Russell JC, Ochoa K, Fulton RS, Fulton LL, Jones C, Boop FA, Broniscer A, Wetmore C, Gajjar A, Ding L, Mardis ER, Wilson RK, Taylor MR, Downing JR, Ellison DW, Zhang J, Baker SJ. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet
2014; 46 (5): 444–50.
Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U, Zuccaro J, Agnihotri S, Ryall S, Barszczyk M, Chornenkyy Y, Bourgey M, Bourque G, Montpetit A, Cordero F, Castelo-Branco P, Mangerel J, Tabori U, Ho KC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis MA, Zagzag D, Foreman NK, Donson A, Hegert JV, Smith A, Chan J, Lafay-Cousin L, Dunn S, Hukin J, Dunham C, Scheinemann K, Michaud J, Zelcer S, Ramsay D, Cain J, Brennan C, Souweidane MM, Jones C, Allis CD, Brudno M, Becher O, Hawkins C. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet
2014; 46 (5): 451–6.
Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, De Jay N, Ramkissoon LA, Corcoran A, Jones DT, Sturm D, Johann P, Tomita T, Goldman S, Nagib M, Bendel A, Goumnerova L, Bowers DC, Leonard JR, Rubin JB, Alden T, Browd S, Geyer JR, Leary S, Jallo G, Cohen K, Gupta N, Prados MD, Carret AS, Ellezam B, Crevier L, Klekner A, Bognar L, Hauser P, Garami M, Myseros J, Dong Z, Siegel PM, Malkin H, Ligon AH, Albrecht S, Pfister SM, Ligon KL, Majewski J, Jabado N, Kieran MW. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet
2014; 46 (5): 462–6.
Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res
2001; 61 (4): 1659–65.
Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer
2011; 11 (6): 426–37.
Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med
2013; 368 (13): 1199–209.
Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature
2013; 497 (7447): 108–12.