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NI FEATURE: PATHOLOGICAL PANORAMA - ORIGINAL ARTICLE
Year : 2016  |  Volume : 64  |  Issue : 1  |  Page : 115-120

Epidermal growth factor receptor (EGFR) gene amplification in high-grade gliomas: Western Indian tertiary cancer center experience


1 Department of Pathology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai, Maharashtra, India
2 Division of Molecular Pathology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai, Maharashtra, India
3 Department of Neurosurgery, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai, Maharashtra, India
4 Department of Pediatric Oncology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai, Maharashtra, India
5 Department of Radiation Oncology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai, Maharashtra, India

Date of Web Publication11-Jan-2016

Correspondence Address:
Sridhar Epari
Department of Pathology, Neuro-Oncology Disease Management Group, Tata Memorial Centre, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.173668

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 » Abstract 

Background: EGFR gene amplification is the hallmark of primary glioblastomas; however, its frequency in patients of Indian origin remains sparsely investigated.
Aims: The aim of this study was to explore the frequency of EGFR amplification in high grade gliomas (HGGs) in Indian patients and to study its correlation with p53 protein overexpression.
Methods and Materials: 324 cases of HGGs, where EGFR gene amplification was evaluated by fluorescence in-situ hybridization formed the study group. Ratio of >2 was considered as EGFR gene amplification. Immunohistochemically, p53 overexpression was evaluated and graded as positive for strong intensity staining in more than 50% of tumour cells.
Results: 249 patients were male and 75 female (M: F-3.3:1); their age range was 8-91 years [paediatric glioblastoma (pGBM; 8-18yrs; n = 24)], adult HGGs [>18yrs; n = 300]}. 258 patients were having a GBM [including 31 with a GBM with oligodendroglioma component (GBM-O)], 31 with a gliosarcoma, 13 with an anaplastic astrocytoma (AA), 12 with an anaplastic oligodendroglioma (AO), and 10 with an anaplastic oligoastrocytoma (AOA). 79/233 cases (34%) with an adult GBM, (including 10/31 with a GBM-O [32.2%]), 1/31 (3.2%) with a GS and 1/10 (10%) with an AOA showed EGFR gene amplification. None of the pGBMs (n = 24) showed amplification. Amplification was seen in 19/81 (23.4%) of diffuse p53 protein positive cases and 53/143 (37%) of cases with focal or negative p53 protein expression.
Conclusions: 34% of our adult GBM patients showed EGFR gene amplification. The amplification was uncommonly associated with a strong diffuse p53 protein expression.


Keywords: Epidermal growth factor receptor; fluorescence in situ hybridization; glioblastoma; high-grade gliomas; MIB-1 labeling index; p53 protein


How to cite this article:
Shelly D, Epari S, Arora I, Pai T, Ahmed S, Moiyadi A, Chinnaswamy G, Gupta T, Goda J, Shetty P, Kane SV, Desai SB, Jalali R. Epidermal growth factor receptor (EGFR) gene amplification in high-grade gliomas: Western Indian tertiary cancer center experience. Neurol India 2016;64:115-20

How to cite this URL:
Shelly D, Epari S, Arora I, Pai T, Ahmed S, Moiyadi A, Chinnaswamy G, Gupta T, Goda J, Shetty P, Kane SV, Desai SB, Jalali R. Epidermal growth factor receptor (EGFR) gene amplification in high-grade gliomas: Western Indian tertiary cancer center experience. Neurol India [serial online] 2016 [cited 2019 Sep 17];64:115-20. Available from: http://www.neurologyindia.com/text.asp?2016/64/1/115/173668



 » Introduction Top


Infiltrating/diffuse gliomas in adults are the most common primary central nervous system (CNS) tumors, constituted by astrocytic and oligodendroglial tumors. Although ependymomas theoretically are part of glial tumors, they are biologically and clinically distinct and are not included in the spectrum of infiltrating/diffuse glial neoplasms. World Health Organization (WHO) classifies glial neoplasms histologically into low-grade (WHO grade II) and high-grade gliomas (HGGs; WHO III and IV).[1]

Glioblastomas (GBMs, WHO grade IV), the most aggressive form of gliomas, are unfortunately the common primary adult CNS tumors. It is considered that the majority of GBMs (>90%) are primary GBMs that arise de novo in older patients without clinical or histopathological evidence of a preexisting, less malignant precursor lesion, whereas secondary GBMs (<10%) manifest in younger patients (mean age, 45 years) and develop from preceding low-grade diffuse astrocytomas (WHO grade II) or anaplastic astrocytomas (WHO grade III).[2] Both these entities are histologically indistinguishable but differ from each other biologically, clinically, and prognostically.[3],[4],[5] Many of the molecular markers have been validated for diagnostic, prognostic, biological, and predictive utility in gliomas over time. Currently, 1p/19q codeletion, IDH1/2 gene mutation, EGFR gene amplification and mutation, phosphatase and tensin homolog (PTEN) alterations, TP53 mutations, O (6)-methylguanine-DNA methyltransferase (MGMT) methylation, and telomerase reverse transcriptase (TERT) promoter gene mutations are being used as part of routine molecular workup in gliomas.[6]

Studies have reported EGFR gene amplification in approximately 35%–50% of GBMs.[1],[2],[7] Most of these data are derived from the studies from Western countries, while the majority of studies reported from India are based on the sample size of approximately 100.[8],[9],[10] Our study is essentially aimed at evaluating the frequency of EGFR gene amplification in HGGs by fluorescence in situ hybridization (FISH) in one of the largest cohorts of Indian patients.


 » Materials and Methods Top


Study sample

In this single-center study, all the diagnosed cases of HGGs from January 2009 to July 2015, in whom results of EGFR gene amplification were available, formed the study sample. Relevant clinical details, that is, age, sex, and location of the tumor, were noted from the electronic medical records of our hospital information system. All the original hematoxylin and eosin–stained slides were reviewed and classified according to the 2007 WHO classification of tumors of the CNS.

Immunohistochemistry (IHC)

Evaluation for p53 protein expression and MIB-1 labeling index (LI) was performed on 3- to 4-µm formalin-fixed paraffin-embedded (FFPE) tissue sections using the Ventana automated stainer by polymer detection kit for p53 (Dako, clone D07; dilution, 1:50) and Ki-67 (Dako; clone MIB-1, dilution, 1:300), respectively, by using the manufacturer's protocol. p53 Protein staining was graded as positive, focal positive, and negative: Positive, if >50% of tumor cells showed staining with strong intensity; focal positive, if 10%–50% of tumor cells showed strong intensity staining or >50% of cells showed moderate-intensity staining; and negative, if there was the presence of an occasional cell with weak or moderate intensity or no staining. MIB-1 LI was expressed as percentage of tumor cells labeled in the highest proliferating areas.

Fluorescence in situ hybridization

EGFR gene amplification was done using dual-color probe comprising locus-specific identifier probes for EGFR spectrum, that is, Orange/CEP7 Spectrum Green Probe from Vysis (Abbott Laboratories, Downers Grove, IL, USA) on 3-µm representative tumor FFPE sections mounted on double poly-L lysine-coated slides and incubated overnight at 60°C. After incubation, deparaffinization was done by incubating overnight at 60°C followed by two changes in xylene at 56°C and one change at room temperature, with subsequent dehydration with two changes of absolute alcohol each for 5 minutes. Pretreatment was done with 2.5% sodium thiocyanate for 5 minutes and with sodium citrate buffer in microwave at 900 W for 4 minutes. Sections were then air-dried followed by digestion with 0.2 g of pepsin dissolved in 10 mM HCl in a water bath at 37°C for 25 minutes. Slides were subjected through increasing alcohol gradations (70%, 85%, and 100%) and dried at 45°C before addition of the probe. Five microliters of the probe was directly added to the tissue sections, and slides were initially denatured at 80°C for 5 minutes followed by incubation at 37°C for 16–20 hours for hybridization in Thermobrite slide incubator. Post-hybridization was done by washing with 1.5 M urea/0.1 X SSC (sodium chloride–sodium citrate solution, pH 5.3) at 45°C for 15 minutes, and finally counterstained with diamidino-2-phenylindole (DAPI) and stored in freezer. The sections were viewed under an Olympus B × 53F upright fluorescence microscope equipped with appropriate excitation and emission filters allowing visualization of the orange and green signals (QLCam Olympus camera and Qcapture pro 7.0 image analyzer software). For all cases, at least 100 nonoverlapping tumor cell nuclei were evaluated, and the numbers of EGFR (red) and CEP7 (green) signals/nuclei were recorded. The mean signal number for the EGFR gene (red) and CEP7 (green) was calculated for each case, followed by the calculation of EGFR gene/CEP7 ratio. The EGFR gene was quantified as amplified when the mean tumor cell EGFR/CEP7 signal ratio was greater than 2 or when EGFR gene (red) signals were seen in large clusters. Chromosomal gains or polysomies were defined as more than 10% of nuclei containing three or more signals for locus or CEP.[11]

Statistical analysis

The chi-square test was performed to reveal any significant correlation between EGFR amplification, p53 overexpression, MIB-1 labeling index (LI), and necrosis.


 » Results Top


Study sample

A total of 324 cases formed the study sample [Table 1]. This included 249 male and 75 female patients (male-to-female ratio, 3.3:1). Their age ranged from 8 to 91 years (pediatric GBM [pGBM]: 8–18 years; n = 24, adult HGG >18 years; n = 300). Of the 324 cases, 258 were having a GBM (including 31 with a GBM with oligodendroglioma component [GBM-O]), 31 a gliosarcoma (GS), 13 an anaplastic astrocytoma (AA), 12 an anaplastic oligodendroglioma (AO), and 10 an anaplastic oligoastrocytoma (AOA). One case of GBM did not reveal any signal on FISH and was excluded; thus, the total study sample included 323 cases. Their detailed histopathological distribution is summarized in [Table 1] and [Figure 1].
Table 1: Histological distribution of cases

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Figure 1: Frequency distribution of EGFR gene amplification in different histological high-grade glioma subtypes (a) and age-groups (b)

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EGFR gene amplification

EGFR gene amplification was seen in 81 of 323 (25%) cases of HGG (WHO grade III and IV; [Figure 1] and [Figure 2]). None of the pGBM (0/24; [Figure 3]c and [Figure 3]d), AO (0/12; [Figure 3]e and [Figure 3]f), and AA cases (0/13) showed amplification. In total, 79 of 233 cases (34%) of adult GBMs (including 10/31 of the GBM-Os [32.2%]), 1 of 31 cases (3.2%) of GSs ([Figure 3]a and [Figure 3]b), and 1 of 10 cases (10%) of AOAs ([Figure 2]g and [Figure 2]h) showed EGFR gene amplification [Figure 1]. Chromosome 7 polysomy was noted in four cases of adult GBMs, who were otherwise EGFR nonamplified.{Figure 1}
Figure 2: Representative photomicrographs of glioblastoma cases (a, d, g: HE, ×200; inset in figure: HE, ×400) with respective immunohistochemistry for p53 protein (b, e, h: IHC, ×200; b: Negative, e: Focally positive, and

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Figure 3: Photomicrographs representative of gliosarcoma (a: HE, ×100; b: EGFR FISH), pediatric glioblastoma (c: HE, ×100; d: EGFR FISH), anaplastic oligodendroglioma (e: HE, ×100; f, EGFR FISH), and anaplastic oligoastrocytoma (g: HE, ×100; h: EGFR FISH) with respective EGFR-nonamplified results

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Clinical parameters [adult GBM]

The age of the patients showing EGFR amplification ranged from 21 to 91 years, with the maximum number of cases (82.2%; 65/79) being clustered in the age-group of more than 40 years. In the 18- to 40-year age-group, 28% (14/50) of patients showed an EGFR amplification. None of the 24 pediatric GBM cases (pGBM) showed an EGFR gene amplification [Table 2]. The detailed age-wise distribution is presented in [Figure 2]. Male-to-female ratio of EGFR gene-amplified cases was 3.6:1 [Table 2] and [Figure 2].
Table 2: Clinical parameters for EGFR-amplified and nonamplified adult GBMs

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Histological parameters (adult GBMs)

A total of 74.6% (59/79; [Figure 2]) of EGFR amplified and 72.4% (129/154) of EGFR-nonamplified cases showed necrosis. The statistical correlation between EGFR amplification and necrosis was insignificant (P = 0.53).

Immunohistochemical parameters [adult GBMs]

The total number of cases with interpretable p53 protein expression was 224 [Table 3] and [Figure 2]. EGFR amplification was seen in 23.4% (19/81) of p53 protein-positive cases [Figure 2]g,[Figure 2]h,[Figure 2]i, 38.6% (34/88) of p53-focally positive cases [Figure 2]d,[Figure 2]e,[Figure 2]f, and 34.5% (19/55) of p53-negative cases [Figure 2]a,[Figure 2]b,[Figure 2]c. The statistical correlation between variable p53 protein expression and EGFR amplification was insignificant (P = 0.09). However, EGFR amplification of p53-nonpositive group (i.e., combined group of focally positive and negative cases) was 37% (53/143), which showed statistically significant correlation (P = 0.03) on comparing with the p53-positive group, which was 23.4% (19/81). The statistical correlation was, however, not significant (P = 0.66) on comparing EGFR amplification of the combined group of p53-positive and p53-focally positive (31.7%) cases with the p53-negative (34.5%) group [Table 3] and [Figure 2].
Table 3: Histological and immunohistochemical parameters of adult GBMs (n=233)

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MIB-1 LI values were interpreted in 191 cases, which ranged from 8%–60%. EGFR amplification was seen in 13.3% (2/15) of cases with MIB-1 LI <10%, 39% (41/105) of cases with MIB-1 LI of 10%–20%, and 35.2% (25/71) of cases with MIB-1 LI >20%. No statistically significant correlation was seen between MIB-LI and EGFR amplification (P = 0.15; [Table 3]).


 » Discussion Top


Molecular markers with diagnostic, prognostic, and possible predictive value have been identified in gliomas. These include 1p/19q codeletion, IDH1/2 gene mutation, MGMT methylation, and TERT promoter gene mutations. EGFR gene amplification, although not one of the frontline markers for evaluation, is still considered to be a marker of de novo/primary GBMs, which are known to be more aggressive than secondary GBMs. Sometimes, it is still considered as one of the soft prognostic markers.[6] Different genomic alterations in EGFR gene such as gene amplification, gene rearrangements of variant 3 (EGFRvIII), arising by in-frame deletion of exon 2–7, and point mutations, are also being evaluated; however, all of these are seen only in amplified cases.[6] Currently, the most common and accepted modality to evaluate EGFR gene amplification is FISH.[12] The advantage of FISH is that it allows careful quantification of individual copies noted in single cells/nuclei within the tumor and thus helps in correctly identifying amplification and polysomy, although it does not depict the exact number of times of amplification.

In the current study, we identified EGFR amplification in 34% of adult GBMs. This is in concordance with the English literature, where EGFR amplifications have been identified in 35%–50% of adult GBMs.[1],[2],[6] Jha et al., from India had reported EGFR amplification by FISH in 37.4% of primary GBMs in a cohort of 75 patients aged 41–60 years. However, other Indian studies have reported a frequency of 38%–68% EGFR protein overexpression by immunohistochemistry in gliomas (sample size of 35–58), which is not a true representation of gene amplification.[13],[14] In one of the largest population-based study of 240 cases of GBMs, Ohgaki et al., reported EGFR amplification in 34% of the cases.[5]

Only 1 of 31 GS cases of the present study showed EGFR amplification, thus suggesting an uncommon genetic alteration in GSs. None of our AA cases showed EGFR amplification, although the reported frequency of EGFR amplification in grade III anaplastic astrocytomas is 15%–25% and many of these tumors behave like GBMs.[14] Thus, EGFR gene amplification is considered as a diagnostic marker of GBMs, especially in the cases with under-representative biopsies of HGGs where unequivocal histological features for diagnosing GBMs are absent. In our study, four EGFR-nonamplified cases of GBM showed polysomy 7. Various studies have detected the presence of polysomy 7 in cases of low-grade astrocytomas and pediatric HGGs.[6] However, none of our cases with a pGBM showed polysomy 7.

EGFR amplification was very rare in oligodendroglial tumors, with only a single case (4.5%, 1/22) showing its amplification (which was a case of anaplastic oligoastrocytoma). None of the pure oligodendroglial tumors showed EGFR gene amplification [Figure 3]. Possibly, the EGFR-amplified case of AOA genetically represents a GBM and the histological oligodendroglial component may just be a morphological phenotypic variation. In fact, studies have suggested that EGFR amplification is essentially mutually exclusive with 1p/19q codeletion and IDH gene mutations.[6] Interestingly in our study, the frequency of EGFR amplification observed in GBM-Os (32.2%) was much closer to GBMs (33.1%), and moreover, all these cases of GBM-Os were not 1p19q codeleted (which had been evaluated as a part of routine diagnostic and clinical management); 19 of 31 GBM-O cases were part of our clinical study on GBM-Os, which was earlier published.[15] These findings reemphasize that a GBM-O is more of a morphological variation of GBM rather than part of the spectrum of oligodendroglial tumors.

In the present study, the predominant EGFR-amplified cases (80.2%; 65/81) were seen in the >40-year age-group. None of them was from the pediatric age-group (n = 0/24). The cases of pediatric GBMs (pGBM) included in this study were also part of the 66 patients of the clinical study earlier reported.[16] Only 5 of 43 patients showing EGFR amplification were younger than 30 years. Although the frequencies of EGFR amplification in different age-groups is in concurrence with literature, where EGFR amplification was most commonly seen in patients older than 40 years,[2],[5] the present study showed the occurrence of EGFR amplification (although rare) in younger adults too. Thus, it appears that the phenomenon of EGFR gene amplification in adult GBMs can be seen across different age-groups.

TP53 mutations are known to be one of the earliest detectable genetic alterations and are seen in 59% of low-grade diffuse astrocytomas, 53% of AAs, and 65% of secondary GBMs.[17],[18] p53 Protein overexpression, that is being used as a surrogate marker for TP53 genetic aberrations in clinics, is proficient as a marker but with poor sensitivity and specificity indices for the latter.[19]

In our study, we found EGFR amplification less commonly in cases showing diffuse p53 protein positivity (P = 0.03), which corroborates with the study by Jha et al., where they reported TP53 mutations in 11.8% of cases showing EGFR amplification.[8] Proliferation index, measured by MIB-1 LI, was more than 20% in 71 of 191 GBM cases, and 35.2% of these showed EGFR amplification; however, no significant statistical correlation was seen.

The strength of this study is the inclusion of a large cohort of patients; it is one of the largest Indian studies on EGFR gene amplification in HGGs. However, our study is limited by the lack of data on other molecular markers such as the status of PTEN, IDH1/2 gene mutations, and 1p/19q codeletion (although some of the recent cases had data on IDH and 1p/19q but were not within the scope of the study), the availability of which could have helped us in better subclassifying tumors as primary or secondary GBMs. Nevertheless, the authors believe that EGFR gene amplification by itself is a good marker of primary GBMs, and this study only aimed at evaluating the frequency of EGFR gene amplification.

To conclude, in our series of Indian adult HGG patients, the frequency of EGFR gene amplification was found to be 34%, while it was almost nonexistent in oligodendroglial tumors. More importantly, the frequency of EGFR gene amplification seen in GBM-Os was more akin to GBMs, thus suggesting that GBM-Os are possibly genetically closer to GBMs. It is very uncommon in patients aged <30 years and is nonexistent in pGBMs. EGFR gene amplification is also uncommon in strong diffuse p53 protein expression cases. However, no significant correlation was found with the presence of necrosis and MIB-1 LI.

Acknowledgments

The authors would like to thank the staff of Molecular Pathology Laboratory, ACTREC and Tata Memorial Hospital, especially Mr. Sandeep Dhanavade, Mr. Vinayak Kadam, Ms. Jyoti Bodake, and Ms. Rajni Bagal, for technical assistance in carrying out FISH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO Classification of tumors of the central nervous system. Acta Neuropathol 2007;114:97-109.  Back to cited text no. 1
    
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Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007;170:1445-53.  Back to cited text no. 2
    
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Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013;19:764-72.  Back to cited text no. 3
    
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Kleihues P, Ohgaki H. Primary and secondary glioblastomas: From concept to clinical diagnosis. Neuro Oncol 1999;1:44-51.  Back to cited text no. 4
    
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Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005;64:479-89.  Back to cited text no. 5
    
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Pekmezci M, Perry A. Practical molecular pathologic diagnosis of infiltrating gliomas. Surg Pathol Clin 2015;8:49-61.  Back to cited text no. 6
    
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Maire CL, Ligon KL. Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro Oncol 2014;16:(ppl 8):viii1-6.  Back to cited text no. 7
    
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Jha P, Suri V, Singh G, Jha P, Purkait S, Pathak P, et al. Characterization of molecular genetic alterations in GBMs highlights a distinctive molecular profile in young adults.Diagn Mol Pathol 2011;20:225-32.  Back to cited text no. 8
    
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Das P, Puri T, Jha P, Pathak P, Joshi N, Suri V, et al. A clinicopathological and molecular analysis of glioblastoma multiforme with long-term survival. J Clin Neurosci 2011;18(1): 66-70.  Back to cited text no. 9
    
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Srividya MR, Thota B, Arivazhagan A, Thennarasu K, Balasubramaniam A, Chandramouli BA, et al. Age-dependent prognostic effects of EGFR/p53 alterations in glioblastoma: Study on a prospective cohort of 140 uniformly treated adult patients. J Clin Pathol 2010;63:687-91.  Back to cited text no. 10
    
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Korshunov A, Sycheva R, Golanov A. Molecular stratification of diagnostically challenging high-grade gliomas composed of small cells: The utility of fluorescence in situ hybridization. Clin Cancer Res 2004;10:7820-6.  Back to cited text no. 11
    
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Lopez-Gines C, Gil-Benso R, Ferrer-Luna R, Benito R, Serna E, Gonzalez-Darder J, et al. New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile. Mod Pathol 2010;23:856-65.  Back to cited text no. 12
    
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Sarkar C, Sinha S, Sharma MC, Kumar R, Mehta VS. Supratentorial glioblastoma in adults: Identification of subsets and their clinical correlation. Brain Tumor Pathol 2004;21:7-12.  Back to cited text no. 13
    
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Soni P, Husain N, Awasthi R, Chandra A, Ojha BK, Gupta RK. Revisiting epidermal growth factor receptor in glioblastoma multiforme: Does it play a role in response to therapy? Indian J Pathol Microbiol 2014;57:390-5.  Back to cited text no. 14
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Goda JS, Lewis S, Agarwal A, Epari S, Churi S, Padmavati A, et al. Impact of oligodendroglial component in glioblastoma (GBM-O): Is the outcome favourable than glioblastoma? Clin Neurol Neurosurg 2015;135:46-53.  Back to cited text no. 15
    
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Jalali R, Rishi A, Sridhar E, Jayant SG, Gurav M, Sharma P, et al. Clinical outcome and molecular characterization of pediatric glioblastoma treated with postoperative radiotherapy with concurrent and adjuvant temozolomide: A single institutional study of 66 children. Neurooncol Pract 2015; doi: 10.1093/nop/npv024.  Back to cited text no. 16
    
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Bögler O, Huang HJ, Kleihues P, Cavenee WK. The p53 gene and its role in human brain tumors. Glia 1995;15:308-27.  Back to cited text no. 17
    
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Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 1996;6:217-24.  Back to cited text no. 18
    
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Newcomb EW, Madonia WJ, Pisharody S, Lang FF, Koslow M, Miller DC. A correlative study of p53 protein alteration and p53 gene mutation in glioblastoma multiforme. Brain Pathol 1993;3:229-35.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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