Maria Grazia Bruzzone; Marica Eoli; Valeria Cuccarini; Marina Grisoli; Lorella Valletta; Gaetano Finocchiaro
In recent years the amount of information concerning the genetics and the biology of gliomas, and particularly of glioblastoma multiforme, increased steadily. Such an increase has been paralleled by the technological progress of MRI. The merging of these scientific areas, as summarized in this review, is helping the stratification of glioma patients for clinical trials and their clinical follow-up. Although available therapeutic options appear limited in number, it is likely that in the next 5 years, both as a consequence of the increased knowledge due to genomic sequencing of hundreds of glioblastoma specimens and to continuous improvements of MRI, new perspectives will be available for these patients, with a sizable impact on their prognosis.
Gliomas, the most frequent tumors occurring in the CNS, are defined and graded on the basis of histological features, and pathology is fundamental to predict prognosis and guide the correct patient management. However, pathological diagnosis can be rather subjective and allows considerable interobserver variability, especially in the case of gliomas with mixed histological features. In addition, gliomas of identical histology may be associated with different genetic alterations. Therefore, owing to biological heterogeneity, the histological diagnosis and expected clinical outcome do not match in a significant number of patients and the histological examination does not distinguish tumors responding or not responding to the therapy. Throwing light upon individual biological alterations, molecular analyses may detect subsets of morphologically identical tumors with different clinical behavior (diagnostic markers), describing their prognosis more effectively (prognostic markers). Moreover, molecular biological studies may lead to the discovery of gene-based predictors of therapeutic response, helping to guide more rationally currently available therapies (predictive markers). At present few tumor biomarkers are available for gliomas and it is sometimes unclear how to incorporate molecular genetic information into clinical practice. Differences in study design, patient and specimen characteristics, assay methods and statistical analysis make different studies poorly comparable and also make it difficult to understand the context in which the conclusion should be applied.
Molecular alterations associated with cancer may confer to the tumor physical or biochemical characteristics that can be imaged: contrast enhancement, reflecting blood–brain barrier breakdown, is a key variable (even though its decrease should not be assimilated to a successful treatment). MRI is commonly used in the diagnosis, characterization and clinical management of gliomas for its ability to extract structural, physical, biochemical and functional information. Since histologically similar tumors often show different distinct imaging patterns on MRI, some authors have tried to correlate imaging findings with molecular markers. Despite the fact that many of the imaging features that characterize tumors currently lack biological or molecular correlates,[8–11] phenotypic diversity of gliomas at neuroimaging reflects underlying inter- and intra-tumoral gene expression differences and may be associated with overall survival (OS). Glioblastoma Multiforme & Grade III Astrocytomas
Glioblastoma multiforme (GBM) is the most common adult brain tumor, accounting for more than half of all gliomas. GBM can arise de novo (primary GBM) without clinical, radiological or histopathological evidence of a pre-existing precursor lesion or after progression from a lower grade glioma (secondary GBM). In adults older than 50 years the vast majority of cases are primary GBM, while secondary GBM typically develop in younger patients.
From a molecular perspective, primary and secondary GBM can be considered as two different tumor subtypes. Loss of heterozygosity (LOH) on chromosome 10q is the most frequent genetic alteration in GBM occurring at similar frequencies in primary and secondary GBM (60–80%).[13,14] However, most primary GBM show extensive LOH or loss of the entire chromosome 10, while secondary GBM show partial or complete loss of chromosome 10q, but no loss of 10p. The most common deleted loci are located on regions 10q23–24 where PTEN maps, and on 10q25pter. PTEN mutations occur almost exclusively in primary GBM.
Furthermore, loss-of-function mutations in the p53 protein are found in more than 65% of low-grade astroctytomas, anaplastic astrocytomas and secondary GBM, suggesting that this is an early event in the formation of these tumors. On the other hand, primary GBM infrequently display mutations in p53 (
Mutations in TP53, as well as EGF receptor (EGFR) overexpression/amplification are often mutually exclusive events. Amplification of the EGFR gene (located on chromosome 7p12) occurs in 35–50% of primary GBM and rarely in secondary GBM. Overexpression of EGFR is also more common in primary (80%) has been found, associated with LOH of chromosomal regions on 1p and 19q.
Tumors with 1p and 19q deletions have noteworthy imaging features: they are more likely to have mixed signal intensity on T1 and T2 images, ill-defined margins on T1-weighted MRI and calcifications; when they show contrast enhancement transformation to a higher histological grade is suggested.[45,46]
Ricard et al. (2007) investigated the growth kinetics of 68 low-grade gliomas (LGG) on serial MRI, evaluating the changes in mean tumor diameter. Before initiation of chemotherapy, progressive continuous growth of LGG was observed, with a significantly slower slope in 1p19q-codeleted tumors as compared with 1p19q-retained tumors. The duration of the decreasing slope of the tumor volume in codeleted gliomas led to a lower rate of relapse and to a higher rate of objective response.
Merrell et al. described two cases of ODs with bony metastasis (a very rare occurrence) in patients with deletions of both chromosomes 1p and 19q. Both patients did not have radiological evidence of intracranial progression. The surprising finding might be explained with the prolonged survival of OD patients associated to pronounced tumor chemosensitivity, allowing a long-standing tumor to progress to higher grade, thus contributing to the increased number of metastatic ODs reported in the literature. It is otherwise possible that tumors with this genetic subtype are more prone to metastasis, as deletions are often associated to polyploidy: this pattern is more frequent in the high-grade and/or recurrent ODs. Diffuse Astrocytomas
Well differentiated, diffuse infiltrative astrocytomas include WHO classification grade II astrocytomas and represent approximately 25% of astrocytomas. According to the prevailing cell type, three mayor variants within WHO grade II diffuse astrocytomas can be distinguished: fibrillary, protoplasmatic and gemistocytic astrocytomas. Molecular data on diffuse astrocytomas are limited and their clinical value is still debated, owing to the lack of definitive evidence emerging from the literature.
Approximately 50% of diffuse astrocytomas show mutations of the TP53 gene, which is often associated with LOH on 17p.[53,54] The absence of a wild-type p53 is, therefore, the most common abnormal finding in WHO grade II astrocytomas, resulting in a nonfunctional p53 pathway. Gaiser et al. recently studied 23 diffuse astrocytomas, 11 of which had a TP53 mutation and 12 were the TP53 wild-type, by PCR amplification of genomic DNA extracted from tumor tissues and microvessel computed counting. Intratumoral or peritumoral microvascular hot spots were assessed and analyzed. No association between microvessel density (MVD) and p53 immunohistochemical status was found; however, the MVD was significantly increased in p53 mutated, low-grade astrocytomas. Furthermore, the absolute vessel number was significantly higher in p53 mutated than in p53 wild-type low-grade astrocytomas. No correlation with imaging patterns was observed in this series.
Ware et al. (2007) studied 22 patients with gliomatosis cerebri and found that subjects whose tumors had contrast enhancement and those with tumors harboring +7/-10q, -10q or -13q copy number aberrations had shorter survival times: the study suggested that these risk factors are independent of each other.
With the objective of investigating the utility of CXCR4, a chemokine receptor-mediating glioma cell invasiveness, as a molecular marker for peritumoral disease extent in high-grade gliomas, Stevenson et al. characterized the expression profile of CXCR4 in a large panel of tumor samples. T1-post-contrast and T2-weighted MRI brain scans were used to generate voxel signal-intensity histograms that were quantitatively analyzed to determine the extent and intensity of peritumoral signal abnormality as a marker of disseminated disease in the brain. CXCR4 expression was markedly elevated in grade III and IV tumors compared with grade II gliomas. Significantly, when patients with GBM were segregated into two groups based on CXCR4 expression level, the authors observed a statistically significant increase in the intensity and extent of peritumoral MRI signal abnormalities associated with CXCR4 high-expressing gliomas.
Loss of MGMT expression as a result of promoter hypermethylation is detected more frequently in LGGs than in glioblastomas, with incidence ranging from 50 to 90%. The majority of grade II astrocytomas with MGMT promoter hypermethylation contain TP53 mutations; in particular, G:C A:T transitions.
In LGGs, MGMT promoter hypermethylation seems to influence the natural history of the disease. In fact, the PFS of LGG patients with MGMT promoter hypermethylation is shorter than that of patients without MGMT hypermethylation.[58,59] Furthermore, MGMT hypermethylation is significantly more frequent in glioblastoma that progressed from LGG (i.e., secondary glioblastoma) than in glioblastoma arising de novo (77 vs 28%; p = 0.002).[26,60] These observations suggest that loss of MGMT expression due to promoter hypermethylation frequently occurs at an early stage of the disease. Treatment with temozolomide could reverse the prognostic significance of MGMT hypermethylation in LGGs. In patients treated with temozolomide and hypermethylated MGMT, PFS was longer.
Intriguingly, one recent study describing the integrated genomic analysis of 22 GBMs showed for the first time somatic mutations of isocitrate dehydrogenase 1 (IDH1), which are likely to become the most reliable genetic marker for secondary GBM, confirming that these two GBM subtypes, in spite of histological similarities, are genetically and clinically distinct entities.[61–64] High frequencies of IDH1 mutations have been detected in secondary GBM (50–82%) and not in primary GBMs (3–5%), and are highly frequent in ODs, OAs (65–94%) and diffuse astrocytomas (54–88%).
Genetics and MRI have a growing role in the management of patients who are affected by gliomas. They complement histology and are becoming essential tools for making decisions on the treatment and for the definition of disease relapse: this is critical since PFS is one of the main goals of clinical trials for this disease. In terms of markers, we currently have at least four that have been validated in many ways, both clinically and preclinically: MGMT methylation, EGFR amplification, LOH of 1p and 19q, and p53 mutations. However, individual decision-making based on the status of one or more of such markers may be problematic. However, the combination of MRI findings may corroborate clinical decisions, thereby providing them with a rational basis. Functional MRI techniques, such as perfusion-weighted imaging, magnetic resonance spectroscopy and even spectral analysis, may flank nuclear medicine in this context.
The number of markers of potential clinical impact in the treatment of gliomas is obviously growing. Their validation in clinical use, however, should be carefully evaluated in large, well-organized Phase II and III clinical trials. Patient stratification on their basis will become increasingly relevant. At the clinical level, it is also expected that MRI may play an important role in defining criteria for response to novel treatment, particularly those based on antiangiogenic factors, such as bevacizumab, and those based on the elicitation of specific immune responses (e.g., dendritic cell immunotherapy and peptide-based immunotherapy) as, at present, the criteria to define a response or a relapse in the new scenario that these treatment have created are far from unequivocal. At the preclinical level, it is also anticipated that new reagents, such as contrast media,[65,66] derived from nanotechnologies, will begin to play a new role and help to enter into the new era of molecular imaging.
Genetic patterns are associated with MRI, some of them with sensitivity to therapies and/or survival.
Single genes can be associated with MRI.
Inter- and intra-tumor gene and MRI heterogeneity.
MRI must contain at least T1-weighted nonenhanced and contrast-enhanced, and T2-weighted images.
As a more sophisticated measure of tumor vascularity, it may be hypothesized that cerebral blood volume may be a better predictor of outcome than contrast enhancement.
Advanced MRI techniques would be useful.
Most studies concern glioblastoma multiforme, but the dissociation between pathology and molecular genetics is greatest in low-grade gliomas and surrogate MRI features are needed.
Further studies are needed to establish the role of such markers in each type of glioma; the available data support the utility of tumoral gene-image maps and imaging surrogates as diagnostic and prognostic markers that allow pretreatment evaluation of gliomas.
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