The current treatment of glioblastoma patients based on surgery, radiation, and chemotherapy has achieved modest improvement in progression-free survival. In this direction, personalized treatment is the next achievement for better patient management and increased overall survival. Genetic characterization of high-grade gliomas by MR imaging is the goal in neuroimaging. The main genetic alterations described in these neoplasms, implications in patient treatment, and prognosis are reviewed. MR imaging features and novel techniques are correlated with the main genetic aspects of such tumors. Posttreatment phenomena, such as pseudoprogression and pseudoresponse, are analyzed in association with the genetic expression of these tumors.
Key points
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The inability of the traditional histopathologic brain neoplasm classification to define prognosis and treatment response determined the development of the genomic classification of brain neoplasms and radiogenomics.
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The major clinical importance of this molecular classification is that the same histopathologic type of brain tumor, glioblastoma multiforme, has different treatment response based on the molecular subtype classification.
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The same histopathologic tumor may differ in the molecular component and demonstrate different clinical behavior and outcome.
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Gene characteristics might be a better predictor of key outcomes than histopathologic classification.
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MR imaging findings may be correlated with molecular mutations of brain neoplasms and glioblastoma molecular subtypes.
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Radiogenomics is the combination of imaging and gene expression characteristics of brain neoplasms that has the potential to give insight into tumor biology.
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The major clinical importance of molecular classification of brain tumor, especially glioblastoma, is the capacity to evaluate treatment response, patient outcome, and prognosis.
Introduction
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. They account for 50% to 60% of all astrocytic gliomas, with an incidence of around 5 cases per 100,000 patients per year. Despite significant advances in treatment with aggressive multimodal therapy, GBM remains a deadly disease with a dismal prognosis, with a 2-year overall survival less than 10% and a median overall survival duration of 16 to 17 months. The current standard of care is based on targeted surgical resection followed by concomitant radiation therapy and temozolomide (TMZ) treatment. In recurrent cases, this treatment regimen is commonly followed by antiangiogenic therapy. Nevertheless, after this new therapy approach, only a slight increase in overall survival has been observed, improved from 10 months to 16 to 17 months.
The identification of molecular genetic biomarkers has considerably increased the current understanding of glioma genesis, prognosis, evaluation, and treatment planning. Recent publications have pointed out that gene characteristics might be better predictors of key outcomes than histopathologic classification. Genetic and cellular features of high-grade glioma aggressiveness influence MR imaging. The heterogeneous aspect depicted by MR imaging can be secondary to underlying differences in intratumoral tissues and genetic expression patterns. Improvement in treatment strategies has largely been based on the substantial progress in the identification of genetic alterations or profile in GBMs, which may enable the development of more individualized and specifically targeted therapy.
Introduction
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. They account for 50% to 60% of all astrocytic gliomas, with an incidence of around 5 cases per 100,000 patients per year. Despite significant advances in treatment with aggressive multimodal therapy, GBM remains a deadly disease with a dismal prognosis, with a 2-year overall survival less than 10% and a median overall survival duration of 16 to 17 months. The current standard of care is based on targeted surgical resection followed by concomitant radiation therapy and temozolomide (TMZ) treatment. In recurrent cases, this treatment regimen is commonly followed by antiangiogenic therapy. Nevertheless, after this new therapy approach, only a slight increase in overall survival has been observed, improved from 10 months to 16 to 17 months.
The identification of molecular genetic biomarkers has considerably increased the current understanding of glioma genesis, prognosis, evaluation, and treatment planning. Recent publications have pointed out that gene characteristics might be better predictors of key outcomes than histopathologic classification. Genetic and cellular features of high-grade glioma aggressiveness influence MR imaging. The heterogeneous aspect depicted by MR imaging can be secondary to underlying differences in intratumoral tissues and genetic expression patterns. Improvement in treatment strategies has largely been based on the substantial progress in the identification of genetic alterations or profile in GBMs, which may enable the development of more individualized and specifically targeted therapy.
Radiogenomics
An intriguing characteristic of glial brain tumors is their phenotypic variety. No isolated genetic event accounts for gliomagenesis, but rather the cumulative effects of several alterations that operate in a concerted manner and are responsible for the phenotypic and genotypic heterogeneity of these tumors. Radiogenomics can be referred to as a combination of imaging and gene expression and has the potential to give insight into tumor biology, which is harder to obtain from other techniques alone.
Glioblastoma was the first human cancer sequenced by The Cancer Genome Atlas (TGCA) network effort, resulting in a comprehensive characterization of the mutational spectrum of this neoplasm. TCGA is a project supervised by the National Cancer Institute and the National Human Genome Research Institute to catalog genetic mutations responsible for cancer, using genome sequencing. It is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies. The overarching goal is to improve the ability to diagnose, treat, and prevent cancer ( https://wiki.nci.nih.gov/display/TCGA/The+Cancer+Genome+Atlas ). The TCGA project has been established to generate a comprehensive catalog of genomic abnormalities driving tumorigenesis.
Microarray is a tool used to characterize genomewide gene expression based on messenger RNA levels. This technique has been used to assess the correlation between gene-expression levels, MR imaging features, and outcome in GBM patients. Radiogenomics has been defined as the combination of imaging features and gene expression and has the potential to give insight regarding tumor biology, which may in turn be important to predict management and outcome.
Genetic evaluation of brain tumors
Great strides have been made in the characterization of regional GBM genetic expression patterns. Because of integrated genomic analysis, molecular classifications have been proposed with the intent of providing more uniform neoplasm subclasses from a biological standpoint. Imaging correlates of gene expression may provide important insight into brain tumor biology. Continued genomic sequencing may contribute to patient selection for trials and to developing more specific targeted therapies.
O 6 -Methylguanine-DNA Methyltransferase
Epigenetic silence of the DNA repair O 6 -methylguanine-DNA methyltransferase (MGMT) by promoter methylation is associated with a loss of its expression and has been related to longer overall survival in patients with high-grade gliomas. Those patients treated with concomitant radiation therapy and alkylating agents, such as TMZ, have higher median survival (21.7 months) and 2-year survival (46%) rates when compared with those with unmethylated tumors. Alkylating agents are highly reactive drugs that cause cell death by binding to DNA. MGMT inhibits the killing of tumor cells by alkylating agents by encoding a DNA repair protein to reverse alkylation at the DNA O 6 position of guanine, thereby averting the formation of lethal crosslinks. A promoter controls MGMT activity, and methylation silences the gene in the neoplasm and thus diminishes DNA-repair activity. Through this mechanism, MGMT causes resistance to alkylating drugs ( Fig. 1 ).
Methylation of the MGMT promoter in gliomas can be a useful predictor of tumor responsiveness to alkylating agents. MGMT promoter methylation is an independent favorable prognostic factor that has been associated with longer survival in patients with newly diagnosed high-grade glioma after TMZ chemotherapy. Patients whose tumor contained a methylated MGMT promoter benefited from TMZ, whereas those with unmethylated tumors showed less benefit. Thus, MGMT methylation status may allow the selection of patients most likely to benefit from alkylating therapy. For those patients with unmethylated MGMT, alternative treatments using drugs with different mechanisms of action or methods of inhibiting MGMT should be used.
The level of MGMT varies widely among different tumor types as well as among various samples of the same type of neoplasm. Approximately 30% of gliomas lack MGMT, which may increase tumor sensitivity to alkylating treatment. High levels of MGMT in cancer cells may create a resistant phenotype to alkylating agent treatment, which may become an important determinant of treatment failure. The degree of intratumoral methylation varies among patients. The extent of methylation within the tumor has an association with survival. The degree of methylation impacts prognostic stratification directly, whereby the greatest methylation degree has the longest survival. In a prior study, authors suggest that a cutoff level of 9% could be used to discriminate outcome between methylated and unmethylated tumors. Moreover, a methylation degree greater than 30% could benefit more tumors.
MGMT promoter methylation plays a key role in mechanisms conferring resistance to treatment with alkylating agents. Determination of the methylation status of the MGMT promoter may become an important molecular tool for identifying patients most likely to respond to the treatment and that might allow individually tailored therapy. The methylation status of the MGMT promoter is determined by a polymerase-chain-reaction–specific analysis of tumor samples. Furthermore, new treatment regimens can be proposed using drugs capable of reactivating hypermethylated tumor suppressor genes or deactivating tumor promoting genes.
Isocitrate Dehydrogenase 1
Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been associated with improved outcome in patients with high-grade gliomas. A better prognosis and reduced aggressiveness have been generally reported in glioma patients carrying IDH mutation. Glioma patients with IDH1 mutations have a greater 5-year survival rate than patients with wild-type IDH1 gliomas (93% vs 51%). Prior articles have reported treatment benefits for patients with IDH1 gene mutations. Early radiation therapy appears to be beneficial only in low-grade astrocytoma with IDH mutations. IDH mutations have also been correlated with a higher rate of objective response to TMZ.
Somatic mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in primary brain cancers. These mutations result in the substitution of the arginine 132 codons by histidine in IDH1, which causes alterations in the normal enzymatic activities. IDH1 mutations are associated with alterations in DNA methylation of isocitrate, resulting in overproduction and accumulation of the putative oncometabolite 2-hydroxyglutarate (2-HG). IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis partially through induction of the angiogenesis pathway ( Fig. 2 ).
Among low-grade gliomas, the incidence of mutation of arginine 132 (R132) in the IDH1 enzyme is much more evident and has been reported in more than 85% of grade II and III gliomas. In a recent genome-wide analysis, mutations at codon 132 of IDH1 were found in less than 10% of primary GBMs, whereas this frequency is higher among secondary GBMs, accounting for more than 70%. This gene has been associated with a distinct gene expression profile, especially in the proneural subset of glioblastoma, and is considered an independent prognostic indicator in these patients.
The histopathologic difference between primary and secondary GBMs is hard to establish. However, secondary GBMs have subsets of genetic abnormalities different from primary GBMs. Hence, the in vivo detection of 2-HG could be a potential tool used to differentiate primary from secondary GBMs. Noninvasive detection of 2-HG in glioma patients with IDH1 mutations may be of benefit in clinical management, because disease recurrence may be detected and may help in monitoring the treatment response ( Fig. 3 ). IDH1 mutations seem to occur early and are a key event in the pathogenesis of gliomas, with prognostic implications. It also may represent attractive targets for future pharmacologic inhibition.
Some authors have described that MR spectroscopy (MRS) is able to noninvasively measure 2-HG in gliomas and may serve as a potential biomarker for identifying patients with IDH1-mutant brain tumors. Detection of 2-HG by MRS may provide insights into tumor progression and help monitor treatment effects ( Fig. 4 ). Prior reports have stated that this metabolite could be detected in almost all low-grade gliomas as well as in recurrent GBMs. This finding has implications for diagnosis and monitoring treatment targeting IDH mutations. However, this in vivo MRS analysis is a technical challenge because of the complex spin-coupling features, which may lead to false-positive 2-HG detection. Thus, to be performed, the MRS needs special postprocessing software and may clinically not be convenient for application.
More recently, diffusion-tensor MR imaging has been used to noninvasively detect genetic characteristics of gliomas, especially the IDH1 R132H mutation. High fractional anisotropic (FA) values and low apparent diffusion coefficient (ADC) values were shown in a wild-type IDH1 group when compared with a mutation group in grade II and III gliomas. The authors found that, although FA and ADC values can detect IDH1 mutation, the ratio of minimal ADC is the best measurement for this proposal.
Epidermal Growth Factor Receptor
Epidermal growth factor receptor (EGFR) amplification is a common molecular event in high-grade gliomas. Activation of the EGFR pathway in glioblastoma, and its overexpression and amplification, is a very frequent molecular event found in up to 50% of patients. It is associated with invasion and proliferation of neoplasm cells as well as apoptosis and angiogenesis. EGFR-amplified glioblastomas are relatively radiation-resistant and recur more frequently after therapy.
EGFR amplification is more commonly observed in primary than secondary GBMs, especially the classical glioblastoma subtype, found in up to 97% of patients in that subclass. Thus, EGFR inhibitors could be used in the classical subtype of glioblastoma with better efficacy. Some morphologic MR imaging metrics have been correlated with amplification of EGFR. Higher ratios of the volume of T2-hyperintense lesion to the T1-enhancing volume and a decreased T2 border sharpness coefficient (fuzzier borders) have also been associated with EGFR overexpression prediction. Other authors have suggested that this overexpression could be predicted by the ratio of contrast-enhancing tumor to necrotic tumor. More recently, restricted diffusion has also been correlated with EGFR amplification, which could be a simpler analysis to be used in clinical practice, without the need for postprocessing. Restricted diffusion in brain neoplasms can be secondary to increased neoplasm cellularity or ischemia. Moreover, EGFR status information can be used to predict the classical subtype of glioblastoma, which may in turn be useful to tailor therapy in selected patients.
1p19q
Oligodendrogliomas with 1p19q-deleted lesions have a favorable prognosis. In these genotype lesions, a better response to chemotherapy, duration of response to chemotherapy, progression-free survival after radiation therapy, and overall survival have been seen. Combined loss of 1p and 19q appears to define a treatment-sensitive malignant glioma, one which may often be curable with current therapies.
These genotype neoplasms have a predilection for the frontal lobe location; the insular location is more common in lesions, which rarely or never delete 1p19q. The allelic loss of chromosomal arms 1p19q has been associated with indistinct tumor borders in T1-weighted images, which may indicate invasiveness, and mixed signal intensity on T1-weighted and T2-weighted images ( Fig. 5 ). Calcification and hemorrhage might contribute to signal heterogeneity and susceptibility effect. Calcification is common among low-grade oligodendrogliomas and in anaplastic astrocytomas evolved from low-grade neoplasm, associated with 1p19q loss.
YKL-40
Some prognostic factors must be taken into account for management of glioma patients. YKL-40, also denominated human cartilage glycoprotein-39 or CHI3L1, is a gene located on chromosome 1q32 that is considered one of the potential prognostic factors. Its expression has been used as an adjuvant tool to differentiate GBM from anaplastic oligodendroglioma. YKL-40 has the ability to influence the processes of migration, invasion, and angiogenesis that underlie its capacity to stimulate proliferation. In an earlier report, higher YKL-40 expression proved to be a negative prognostic marker associated with a lower response to radiation therapy and shorter overall survival. Thus, the expression of YKL-40 predicts poor outcomes in glioblastoma. When combined with MGMT promoter methylation analysis, the prognostic value of these markers is closely related to the efficacy of adjuvant radiation therapy with chemotherapy, and this may influence patient selection for aggressive treatment regimens.
Molecular Subclasses of High-Grade Glioma
The histopathologic characterization based on the World Health Organization classification still plays an important role in patient management and in defining the corresponding therapeutic approaches in gliomas. However, this classification fails to identify neoplasm subclasses with different aggressiveness within the same tumor grade. The genetic expression profile of brain neoplasms, especially the astrocytic tumors, varies among different degrees of malignancy and even among those of the same grade.
There is an inability to define different patient outcomes because of histopathologic features. Because of integrated genomic analysis, a molecular classification with 4 different subtypes has been proposed with the intent of providing a more uniform molecular subclass classification of GBM. Verhaak and colleagues proposed a gene expression–based molecular classification of glioblastoma of 4 subtypes: proneural, neural, classical, and mesenchymal, and integrated multidimensional genomic data to establish patterns of somatic mutations and DNA copy number.
The classical, mesenchymal, and proneural subtypes are defined, respectively, by aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1. High-level EGFR amplification is seen in the classical subtype and infrequently in other subtypes. Deletion of a region containing the NF1 gene predominantly occurs in the mesenchymal subtype. Two major features of the proneural class are alterations of PDGFRA and mutations in IDH1, in which younger patients are the majority and tend toward longer survival. Overexpression of neuron markers is seen in the neural subtype. The major clinical importance of this molecular classification is that the same histopathologic type of brain tumor, GBM, has a different treatment response based on the molecular subtype classification. Aggressive therapy performed with radiation therapy followed by TMZ showed the greatest benefit in classical GBM patients, whereas this treatment did not alter survival in the proneural subtype. Most known secondary glioblastomas were classified as proneural. Thus, the importance of detecting these subtypes relies on the tailored therapeutic approach that different subtypes may require ( Tables 1 and 2 ).
| Gene Expression | Classical | Mesenchymal | Proneural | Neural |
|---|---|---|---|---|
| EGFR amplification | High level | Infrequent | Infrequent | Infrequent |
| NF1 deletion | No predominance | Predominance | No predominance | No predominance |
| PDGFRA/IDH1 alteration | Minor | Minor | Major | Minor |
| Neural markers expression | Expression | Expression | Expression | Overexpression |
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