LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

  • Authors:
    • Alice Pasini
    • Paolo Iorio
    • Emanuela Bianchi
    • Serenella Cerasoli
    • Anna M. Cremonini
    • Marina Faedi
    • Carlo Guarnieri
    • Graziano Guiducci
    • Luca Riccioni
    • Chiara Molinari
    • Claudia Rengucci
    • Daniele Calistri
    • Emanuele Giordano
  • View Affiliations

  • Published online on: September 20, 2012     https://doi.org/10.3892/or.2012.2047
  • Pages: 2271-2277
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Abstract

We previously described a cohort of grade II oligodendroglioma (OII) patients, in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at a higher risk of relapse. In this study, we evaluated the CpG methylation of the putative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoter in the same OII cohort, to investigate whether a correlation could be found between EMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-three tumor samples from OII patients were collected over a period of 10 years. Seventeen glioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients. The EMP3, O6-methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2) promoter methylation, evaluated by methylation-specific PCR, and the isocitrate dehydrogenase 1 (IDH1) mutation, identified by sequencing, were compared between the OII and GBM histotypes. The EMP3 promoter methylation was correlated with the analysis of LOH 19q, performed by microsatellite amplification, in OII patients. Disease progression-free interval was evaluated in the OII patients with the EMP3 methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 and MGMT promoter methylation was more frequent in OII than in GBM patients, and the IDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes. Both LOH+/- 19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19q and EMP3 gene promoter methylation was observed in the OII patients at a higher risk of relapse. Our results suggest that a total (cytogenetic and epigenetic) functional loss of both EMP3 alleles accounts for the reduced disease progression-free interval in OII patients. Although the small sample size limits the strength of this study, our results support testing this hypothesis in larger cohorts of patients, considering the methylation of the EMP3 gene promoter together with LOH 19q as an indication for treatment with adjuvant therapy ab initio in order to improve the overall survival of OII patients.

Introduction

Oligodendrogliomas (ODGs) are classified by the World Health Organization (WHO) as low-grade gliomas (OII or OIII) (1). Grade II oligodendrogliomas (OII) are rare and slow-growing tumors, and affected patients show long-term survival when treated with surgical resection at diagnosis, even though the majority eventually relapse (2). Presently accepted guidelines for treatment suggest that adjuvant radio- and/or chemotherapy be delayed until there is clinical evidence of disease progression in OII patients (3). However, it has been shown that their risk of relapse may be defined at an earlier stage (4). Traditionally, a low risk of recurrence among low-grade glioma patients has been related to clinical variables, such as age (≤40 years) at diagnosis, seizures at presentation, absence of neurological deficits, a Karnofsky performance status of ≥70, absence of enhancement at CT/MRI, a pre-operative tumor size of ≤5–6 cm and the tumor not crossing the midline (5). Moreover, a well-accepted molecular factor of prognostic significance is the allelic loss [loss of heterozygosity (LOH)] of chromosome 1p, together with 19q (6). Combined deletions of both arms were observed in up to 80% of ODG patients with prolonged survival (79), suggesting that these unstable chromosomal regions carry critical genes whose silencing may define their clinical history. Both the physical loss of a genetic trait and epigenetic silencing, via CpG island promoter methylation, may downregulate or suppress the expression of significant genes in cancer cells compared to normal ones. The epigenetic profiling of brain tumors has indeed significance as a prognostic index (10): e.g., the epigenetic silencing of O6-methylguanine methyltransferase (MGMT, 10q26) correlates with responsiveness to alkylating agents and radiotherapy in glioblastoma (GBM, WHO grade IV) (1113). The 19q region, frequently lost in ODG tumors, harbors putative tumor suppressor genes, such as the epithelial membrane protein 3 (EMP3, 19q13.3) (1419). The function of EMP3 remains unclear; however, its homology to peripheral myelin protein 22 (PMP22) suggests that the protein is implicated in cell cycle regulation and cell-to-cell interactions (17). The EMP3 promoter contains a CpG island, which is methylated in both high-grade astrocytoma and neuroblastoma brain tumors associated with poorer prognosis (14). Demethylating agents have been shown to restore EMP3 expression in neuroblastoma cell lines, with consequent lower in vitro colony formation and reduction of tumor growth in nude mice (14). A methylated EMP3 promoter was found by Li et al in a group of ODG samples with different histological classifications; however, no association between the EMP3 gene promoter methylation, the corresponding protein expression and 19q deletion was found (20). However, Kunitz et al found a significant association between EMP3 promoter methylation and the allelic loss of 19q, consistent with the reduced EMP3 mRNA expression (21). All these findings suggest that EMP3 methylation may occur in ODG together with LOH of chromosome 19q (LOH 19q), although the clinical significance of their co-occurrence remains to be clarified.

We previously described a cohort of OII patients in whom LOH 19q was present in the subgroup at a higher risk of relapse (22). Given this preliminary evidence, in this study, we evaluated the EMP3 gene promoter in the same cohort of patients, to investigate whether CpG methylation of the residual allele promoter is consistent with the physical loss of the homologous allele promoter and whether a correlation can be established between EMP3 cyto- and epigenetic loss and a higher risk of relapse. In addition, we examined the MGMT and cyclooxygenase 2 (COX2), an isozyme of prostaglandin-endoperoxidase synthase 2 (1q25.2q25.3) gene promoter methylation in these patients. MGMT is a gene of interest in high-grade gliomas, namely GBM, as the methylation of its promoter predicts chemosensitivity to alkylating agents; it is also under evaluation in low-grade gliomas (1113,23). The COX2 gene promoter methylation provides epigenetic information regarding genetic regions that are more stable than the 19q arms, both in low- and high-grade gliomas. The methylation of the 3 gene promoters, EMP3, MGMT and COX2, was also evaluated in a small group of primary WHO grade IV gliomas, in order to validate a different epigenetic profile between low- and high-grade gliomas (21). A further characterization between these 2 subgroups was provided by isocitrate dehydrogenase 1 (IDH1) genotyping, as the IDH1 mutation is rare in primary GBM but frequent in OII (24).

Materials and methods

Patients and tumor specimens

This study was carried out in a small homogeneous cohort of WHO grade II oligodendroglioma (OII) patients, an infrequent low-grade glioma subtype. Study participants gave their informed consent to this study. The protocols were approved by the institutional ethics committee in accordance with the ethical standard of Declaration of Helsinki (1964). Samples from 23 patients were collected over a period of 10 years as previously described (22). The age and gender of patients are reported in Table I. Seventeen GBM (WHO grade IV) samples were collected from 15 patients (2 of which were relapses). There were 9 female patients (60%); median age at the time of diagnosis was 62 years (range, 43–80) (Table II). Tumor samples were embedded in paraffin. All histological diagnoses were reviewed by 2 experienced neuropathologists (S.C. and L.R.).

Table I

Summary of OII patient personal data (age and gender), presence of loss of heterozygosity (LOH) of 1p and 19q, EMP3, MGMT and COX2 promoter methylation status and IDH1 genotyping.

Table I

Summary of OII patient personal data (age and gender), presence of loss of heterozygosity (LOH) of 1p and 19q, EMP3, MGMT and COX2 promoter methylation status and IDH1 genotyping.

No.AgeGenderLOH 1pLOH 19qEMP3MGMTCOX2IDH1
133Male++MMUR132H
250Male++MMUwt
343Female++MMUR132H
435Male++MMUNI
551Female++MNSUNI
638Female+MNSUwt
742Female++MMNSR132H
837Male+MMUwt
959Female++MMUwt
1037MaleMMUR132H
1133Female+MMUR132H
1266Male++MNSUR132H
1330MaleMMUR132H
1470Male++MNSUNI
1542Female++MMUR132H
1637Male+NIMMUwt
1738Male++MMUR132H
1837Female+UMUwt
1956FemaleMMUR132H
2069Male++MMUR132H
2145Female++MMUNI
2228Female+MNSUR132H
2339Female++MMUR132G

[i] +, Loss of heterozygosity; −, heterozygosity; NI, not informative; M, methylated; u, unmethylated; NS, no PCR product; wt, wild-type.

Table II

Summary of GBM patient personal data (age and gender), presence of EMP3, MGMT and COX2 promoter methylation status and IDH1 genotyping.

Table II

Summary of GBM patient personal data (age and gender), presence of EMP3, MGMT and COX2 promoter methylation status and IDH1 genotyping.

No.AgeGenderEMP3MGMTCOX2IDH1
156FemaleUUUwt
256FemaleUUUwt
373MaleUMUwt
449MaleUUUwt
543FemaleUUUwt
652FemaleUMUNI
768FemaleUUUwt
857MaleUMUwt
959FemaleMMUwt
1080FemaleUMUwt
1174FemaleUUUwt
1269FemaleUUUwt
1362MaleMUUwt
1462MaleUUUwt
1574MaleMUUNI
1671FemaleUUUNI
1755MaleUUUwt

[i] M, methylated; U, unmethylated; wt, wild-type; NI, not informative.

Genomic DNA extraction

DNA extraction from the paraffin-embedded tissue was performed using the standard procedure with phenol-chloroform from 5 slices (5-μm thick). The paraffin was dissolved with xylene, and any remaining xylene was washed out with ethanol. After overnight protein digestion with proteinase K, the DNA was separated from the organic phase with phenol-chloroform, precipitated with ethanol and resuspended in Tris-EDTA (TE) buffer.

Analysis of gene promoter methylation

The DNA was processed with sodium bisulfite, converting unmethylated cytosine to uracil, as previously described (11). Briefly, 1 μg of DNA was denatured with sodium hydroxide and modified with sodium bisulfite. The DNA samples were then purified with a commercial kit (Wizard DNA Clean-Up System; A7280; Promega, Madison, WI, USA), and again treated with sodium hydroxide to complete the conversion to uracil. Finally, DNA was precipitated with ethanol and resuspended in 30 μl of TE buffer. The methylation status of the genes of interest was determined by methylation-specific PCR (MSP), using 2 sets of primers (Table III), specific for either methylated or unmethylated DNA (25). The total volume for the MSP reaction was 15 μl, comprising 4 mM MgCl2, 0.5 mM of each dNTP, 0.2 μM of each primer, 0.5 unit of Hot Start DNA polymerase and 3 μl of bisulfite-treated DNA. The methylation of the MGMT and EMP3 gene promoters was spot-checked in selected GBM samples by bisulfite sequencing, cloning PCR products using the pGEM®-T Easy Vector System (A1360, Promega). Selective positive clones were sequenced and products were aligned using the BioEdit sequence alignment editor.

Table III

Sequences of primers used for the promoter methylation analysis.

Table III

Sequences of primers used for the promoter methylation analysis.

GenePrimerSequence 5′-3′Annealing temperature (°C)
MGMTUM-F TTTGTGTTTTGATGTTTGTAGGTTTTTGT62
UM -R AACTCCACACTCTTCCAAAAACAAAACA
M-F TTTCGACGTTCGTAGGTTTTCGC
M-R GCACTCTTCCGAAAACGAAACG
EMP3UM -F GAAGAGATGTAGAAGGAGAGTGAGT62
UM -R CTTATCCCTCACTCAAACCTCCATA
M-F GACGTAGAAGGAGAGCGAGC
M-R CCTCGCTCGAACCTCCGTA
COX2UM -F GAGAGGGGATTTTTTGTGTTTTT60
UM -R CCCAAACACTTCCAAAAACC
M-F GAGGGGATTTTTTGCGTTTTC
M-R CCGAACGCTTCCGAAAAC
MGMTBS-F TTTTGATTAGGGGAGIGGT57
BS-R TCTATACCTTAATTTACC
EMP3BS-F GGGAGTAAGAGAGAAGGAGGTTTAG60
BS-R TTAAAAAATCCCAACCCTAAATAAC

[i] F, forward; R, reverse; MSP primers: M, methylation-specific; UM, unmethylation-specific; BS, bisulfite sequencing primers.

Analysis of the IDH1 mutation

IDH1 alterations of the mutational hotspot codon R132 were assessed by sequencing of PCR-amplified fragments. Primers used were 5′-ACCAAAT GGCACCATACGA-3′ (forward) and 5′-TTCATACCTTGC TTAATGGGTGT-3′ (reverse).

Data analysis

Disease progression-free interval (DPI) was defined as the time between surgery and either disease progression or the last follow-up examination. DPI curves were plotted using the Kaplan-Meier method with GraphPad Prism (Version 4.0, GraphPad Software, San Diego, CA, USA).

Results

Analysis of gene promoter methylation

Analysis of gene promoter methylation was performed via MSP, amplifying the 5′-CpG island close to the transcription start site of each gene of interest (Fig. 1A and 1B). Among our 23 OII patients, the EMP3 gene promoter was methylated in 22 samples and unmethylated in 1 sample; MGMT was methylated in 18 samples and no PCR product was scored in 5 cases; COX2 was unmethylated in 22 samples and no PCR product was detected in 1 sample (Fig. 2 and Table I).

As regards our 17 GBM patients, our results showed that the EMP3 gene promoter was methylated in 3 and unmethylated in 14 samples; MGMT was methylated in 5 and unmethylated in 12 samples; COX2 was unmethylated in all the samples (Fig. 2 and Table II).

As a quality control strategy, selected GBM samples in which the MGMT and EMP3 gene promoter methylation was assayed by MSP were re-analyzed by bisulfite sequencing, confirming the MSP results (Fig. 1C).

Analysis of IDH1 mutation

Analysis of the IDH1 mutational hotspot codon R132 was evaluated in the OII and GBM patients. Among our 23 OII patients, 13 samples showed mutated IDH1. In 12 cases, a Arg→His amino acid substitution (codon CGT→CAT change) was observed at residue 132; only 1 sample showed a Arg→Gly mutation (CGT→GGT). The wild-type genotype was observed in 6 samples. Four cases were not informative (Table I).

In our 17 GBM patients, wild-type IDH1 was found in 14 samples, none showed a mutated gene and 3 cases were not informative (Table II).

EMP3 gene promoter methylation vs. LOH 19q

1p/19q allelic loss in OII samples was evaluated by microsatellite amplification as described in our previous study (22). LOH 1p was scored in 18 samples out of the total 23 (Table I). LOH 19q was present in 16 samples out of 22 (1 sample being not informative) (Table I). Concomitant LOH 1p/19q was observed in 14 out of 22 samples. Of the 16 LOH 19q samples, 15 had the EMP3 gene promoter methylation, while only 1 exhibited the unmethylated EMP3 gene promoter (Table I). Moreover, the 6 samples with conserved 19q chromosome arms had a methylated EMP3 promoter (Table I).

LOH 19q and DPI

DPI was evaluated in the 21 OII patients with methylated EMP3 promoter. Among them, 15 showed LOH 19q, while 6 showed conserved chromosome arms. Relapses were observed in 7 LOH 19q patients and in 1 patient who retained both chromosome arms. Analysis of the DPI curves indicated a different risk of relapse depending on LOH 19q status. When this chromosome alteration was present, 55% of patients relapsed, compared to 17% when both chromosome arms were conserved (Fig. 3).

Discussion

We previously described a group of 23 OII patients evaluated for the presence of LOH 1p19q (22). OII is a neoplastic subclass of cancer with an overall more favorable outcome than other brain tumors. However, this outcome is heterogeneous and unpredictable at the individual level (26); thus, the policy to delay adjuvant therapy until clinical evidence of disease progression (3) may fail to treat some patients harboring aggressive tumors. Individuating features indicating the patient's risk of relapse at diagnosis would ensure a better clinical treatment. In our previous study (22), we identified a subgroup of patients with a shorter disease-free interval and LOH 19q, a cytogenetic alteration frequently observed in OII (27,28) but not in GBM (29). We thus decided to evaluate in the same patients the methylation status of the EMP3 gene promoter located in the 19q chromosome region (19q13.3), which has gained increasing interest as it is considered a candidate tumor suppressor gene for solid tumors (15), including brain tumors. The hypermethylated status of the EMP3 gene promoter in low-grade gliomas is known as a molecular feature distinguishing them from highgrade gliomas (20,21). Thus, a reduced expression level of EMP3 resulting from the methylation of its gene promoter has been reported in OII (21), whereas the hyperexpression of EMP3 has been shown in GBM (30,31). Further support of the critical role of EMP3 methylation in distinct glioma subtypes is provided by the observation of its different frequency in primary GBM (pGBM), vs. secondary GBM (sGBM) and grade II and III astrocytomas (AII and AIII) (21). The higher occurrence in the second group supports the idea that sGBM arises from the progression of anaplastic astrocytomas, while pGBM develops de novo via the dysregulation of different genetic pathways (21). This alternative methylation pattern of EMP3 in distinct glioma histotypes (GBM vs. OII) is consistent with the data obtained examining another important tumor suppressor gene, MGMT; its promoter methylation is currently a recognized prognostic marker of: i) disease progression in WHO grade III glioma (23); and ii) response to temozolomide in GBM (1113). In our study, the methylation of the EMP3 gene promoter was detected in 96% of OII patients, but only in 18% of GBM samples (Fig. 2). All the informative OII samples showed the MGMT gene promoter methylation, compared to the 29% observed in GBM (Fig. 2). Further differentiation between these 2 subgroups was provided by IDH1 genotyping: mutated IDH1 was present in approximately 2/3 of the informative OII samples but absent in all the GBM samples; these results are in agreement with those from previous studies (24). The unmethylated status of the COX2 gene promoter in both low- and high-grade gliomas confirms the stability of the genetic region 1q, conserved in both these tumor types, and supports a correlation between chromosome instability and CpG island methylation.

Given the findings in the literature reporting a reduced expression level of EMP3 resulting from the methylation of its gene promoter (21,32), we thus assumed that in OII patients with LOH 19q, methylation of the gene copy located on the residual chromosome arm would imply its silencing, with an unfavorable outcome. Further support of this hypothesis is provided by the report of a more aggressive tumor phenotype associated with EMP3 promoter methylation in neuroblastoma patients (14), and by the finding that the re-expression of EMP3, induced by demethylating agents, is associated with lower tumorigenicity in neuroblastoma cell lines (demonstrated by lower in vitro colony formation and reduced tumor size of xenografts) (14). Our results indicate that the EMP3 gene promoter methylation is a hallmark in OII patients and that when this event occurs in the presence of LOH 19q, a complete (cyto- and epigenetic) functional loss of both EMP3 alleles occurs. Its putative role as a tumor suppressor gene fits well with our findings regarding DPI: a higher risk of relapse was observed in patients with LOH 19q/EMP3 methylation (55%) vs. the patients who, although harboring methylated EMP3, had both 19q chromosome arms conserved (17%) (Fig. 3). The small sample size, collected over a 10-year period at our clinical institution, due to the low frequency of this neoplastic disease, limits the statistical power of this result; nevertheless, our observation discloses a potential molecular explanation for the higher risk of relapse of OII patients with deleted 19q.

In conclusion, the results from our study on OII patients highlight the fact that LOH 19q determines the complete loss of EMP3 function, as the conserved allele is frequently hypermethylated, and this may represent the molecular basis of the higher risk of relapse in this subgroup of OII patients. Testing this hypothesis in a larger number of patients is of clinical relevance to highlight the presence of EMP3 gene promoter methylation together with LOH 19q as an indication for treatment ab initio with adjuvant therapy in order to improve the overall survival of these patients.

Aknowledgements

We are grateful to Ms. Kristina Mayberry for the careful critical editing of the manuscript.

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December 2012
Volume 28 Issue 6

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Spandidos Publications style
Pasini A, Iorio P, Bianchi E, Cerasoli S, Cremonini AM, Faedi M, Guarnieri C, Guiducci G, Riccioni L, Molinari C, Molinari C, et al: LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation. Oncol Rep 28: 2271-2277, 2012
APA
Pasini, A., Iorio, P., Bianchi, E., Cerasoli, S., Cremonini, A.M., Faedi, M. ... Giordano, E. (2012). LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation. Oncology Reports, 28, 2271-2277. https://doi.org/10.3892/or.2012.2047
MLA
Pasini, A., Iorio, P., Bianchi, E., Cerasoli, S., Cremonini, A. M., Faedi, M., Guarnieri, C., Guiducci, G., Riccioni, L., Molinari, C., Rengucci, C., Calistri, D., Giordano, E."LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation". Oncology Reports 28.6 (2012): 2271-2277.
Chicago
Pasini, A., Iorio, P., Bianchi, E., Cerasoli, S., Cremonini, A. M., Faedi, M., Guarnieri, C., Guiducci, G., Riccioni, L., Molinari, C., Rengucci, C., Calistri, D., Giordano, E."LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation". Oncology Reports 28, no. 6 (2012): 2271-2277. https://doi.org/10.3892/or.2012.2047