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  • American Association for Cancer Research (AACR)  (9)
  • 1
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    Abstract 1277: Antigen-specific markers for paraneoplastic neurological syndromes obtained by proteomic analysis of patient immunoglobulins
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1277-1277
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1277-1277
    Abstract: In the antibody response, as occurs in antitumor immunity, germline sequences are rearranged and mutated to generate a sequence with specificity for an antigen. In earlier work, it was shown that the antigen specificity of immune sera from rats can be distinguished by the proteomic analysis of immunoglobulins. It is hypothesized that the sequence of the antigen binding sites converges to a similar subset in individuals exposed to a given antigen. We therefore tested the applicability of our approach in patients with Paraneoplastic Neurological Syndrome (PNS). In these patients, a tumor triggers a well-characterized auto-immune response against onconeural antigens expressed in tumor and the affected part of the nervous system. These antibodies serve as markers for both the underlying tumor and specific neurological syndromes. Sera of 60 patients with PNS associated with paraneoplastic antibodies were analysed: 20 anti-HuD (18 lung cancer), 20 anti-Yo (6 breast, 9 gynecological and one other cancer), 10 anti-amphiphysin (4 lung, one breast and one other cancer), and anti-CV2 (6 lung cancer) antibodies. Antigen-specific immunoglobulins were collected by affinity enrichment on beads coated with recombinant antigen. The antigen-specific immunoglobulins were digested with trypsin and analyzed by nano-LC and mass spectrometry. From the resulting dataset, peptides were selected that uniquely identified one of the patient groups, and the peptide sequence was deduced from fragmentation spectra. 28 specific and unique peptides were found; 0 specific for amphiphysin, 2 specific for CV2, 11 for HuD and 15 for Yo. Several marker peptide sequences showed homology to known immunoglobulin sequences, and no relations were found to other known proteins from the NCBInr protein database. The data show that immunoglobulin-derived biomarkers can indeed be found in samples from patients and can serve as early markers of cancer and auto-immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1277. doi:1538-7445.AM2012-1277
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1277
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
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    Abstract 1228: Spatial transcriptomics: Data processing revisited to address noise interference
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Abstract: Background: Spatially resolved transcriptomics is a novel and already highly recognized method that allows RNA sequencing results to be annotated with local tissue phenotypes. The NanoString GeoMx Digital Spatial Profiling (DSP) Platform allows users to collect RNA expression data from manually selected Regions of Interest (ROIs) on FFPE tissue sections. Here, we extensively evaluated data from the DSP platform with its associated pipeline and identify significant background noise interference issues which compromise data interpretation. Alternative and more suitable workflows are presented for correct data analysis. Methods: In this study, 12 paired tumor samples were collected from six glioma patients who underwent two separate resections. For all patients, the first resection was a low grade astrocytoma (WHO grade II or III) and the second resection was a high grade astrocytoma (WHO grade IV). The DSP platform was used to collect expression data of 1,800 genes from 72 ROIs (i.e. 6 per sample). Biological replicates were made of eight tumors from four patients. Gene expression data was normalized with both standard NanoString methods and several alternative methods (e.g. DeSeq2, gamma fit correction and quantile normalization). Weighted Gene Co-expression Network analysis (WGCNA) was used for biological validation. In addition to our own study, six publicly available NanoString DSP datasets were evaluated. Results: Data distributions of all glioma samples, when exposed to standard data processing, were burdened with significant background noise interference. Notably, differences in noise interference were largest between biologically distinct tumor subgroups (i.e. between first and second glioma resections), which was confirmed in replicate experiments. The noise interference patterns were also present in all six publicly available NanoString DSP datasets which will invariably lead to incorrect interpretation of the underlying biology. To correct for noise interference, we tested several normalization methods. The relatively crude quantile normalization method provided the least biased result and showed the highest concordance with bulk RNA sequencing data. To evaluate the biological validity of our alternative approach, we used T cell counts from our tissue regions as an independent parameter, that were quantified using immune fluorescence. Unsupervised WGCNA identified gene clusters enriched for lymphocyte genes that highly correlated with T cell quantities in ROIs, confirming that alternative normalization can extract a biological signal from the DSP platform. Conclusion: The DSP Platform platform suffers from significant noise interference when using standard analysis tools that obscure its results. Here, we revised the workflow and provide an alternative normalization that adequately addresses noise interference and enables correct interpretation of gene expression data. Citation Format: Levi van Hijfte, Marjolein Geurts, Wies R. Vallentgoed, Paul H. Eilers, Peter A. Sillevis Smitt, Reno Debets, Pim J. French. Spatial transcriptomics: Data processing revisited to address noise interference [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1228.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1228
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
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    Gene Expression Profiles Associated with Treatment Response in Oligodendrogliomas
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 24 ( 2005-12-15), p. 11335-11344
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 24 ( 2005-12-15), p. 11335-11344
    Abstract: Oligodendrogliomas are a specific subtype of brain tumor of which the majority responds favorably to chemotherapy. In this study, we made use of expression profiling to identify chemosensitive oligodendroglial tumors. Correlation of expression profiles to loss of heterozygosity on 1p and 19q, common chromosomal aberrations associated with response to treatment, identified 376, 64, and 60 differentially expressed probe sets associated with loss of 1p, 19q or 1p, and 19q, respectively. Correlation of expression profiles to the tumors' response to treatment identified 16 differentially expressed probe sets. Because transcripts associated with chemotherapeutic response were identified independent of common chromosomal aberrations, expression profiling may be used as an alternative approach to the tumors' 1p status to identify chemosensitive oligodendroglial tumors. Finally, we correlated expression profiles to survival of the patient after diagnosis and identified 103 differentially expressed probe sets. The observation that many genes are differentially expressed between long and short survivors indicates that the genetic background of the tumor is an important factor in determining the prognosis of the patient. Furthermore, these transcripts can help identify patient subgroups that are associated with favorable prognosis. Our study is the first to correlate gene expression with chromosomal aberrations and clinical performance (response to treatment and survival) in oligodendrogliomas. The differentially expressed transcripts can help identify patient subgroups with good prognosis and those that will benefit from chemotherapeutic treatments. (Cancer Res 2005; 65(24): 11335-44)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-1886
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 4
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    Identification of Differentially Regulated Splice Variants and Novel Exons in Glial Brain Tumors Using Exon Expression Arrays
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 12 ( 2007-06-15), p. 5635-5642
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 12 ( 2007-06-15), p. 5635-5642
    Abstract: Aberrant splice variants are involved in the initiation and/or progression of glial brain tumors. We therefore set out to identify splice variants that are differentially expressed between histologic subgroups of gliomas. Splice variants were identified using a novel platform that profiles the expression of virtually all known and predicted exons present in the human genome. Exon-level expression profiling was done on 26 glioblastomas, 22 oligodendrogliomas, and 6 control brain samples. Our results show that Human Exon arrays can identify subgroups of gliomas based on their histologic appearance and genetic aberrations. We next used our expression data to identify differentially expressed splice variants. In two independent approaches, we identified 49 and up to 459 exons that are differentially spliced between glioblastomas and oligodendrogliomas, a subset of which (47% and 33%) were confirmed by reverse transcription-PCR (RT-PCR). In addition, exon level expression profiling also identified & gt;700 novel exons. Expression of ∼67% of these candidate novel exons was confirmed by RT-PCR. Our results indicate that exon level expression profiling can be used to molecularly classify brain tumor subgroups, can identify differentially regulated splice variants, and can identify novel exons. The splice variants identified by exon level expression profiling may help to detect the genetic changes that cause or maintain gliomas and may serve as novel treatment targets. [Cancer Res 2007;67(12):5635–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-2869
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 5
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    Abstract 3936: Identifying molecular subgroups of gliomas in formalin fixed paraffin embedded material
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Abstract: Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Histological classification, combined with the patients’ prognostic features, often guides treatment decisions. Unfortunately, differences in histology are subtle and therefore, diagnosis is subject to a large interobserver variability. To improve classification, we did expression profiling on fresh frozen tumor material of 276 glioma samples of all histological subtypes. This resulted in seven molecular subgroups, which correlated significantly better with survival than histology. When validated in prospective studies these molecular clusters could contribute to clinical decision making. However, there is a lack of fresh frozen glioma material, and until now clinical studies have been performed on formalin fixed paraffin embedded (FFPE) material. Therefore, we would like to see whether our molecular clusters are reproducible in FFPE material. Expression profiling was performed on 57 paired snap-frozen/FFPE glioma samples of all histological and molecular subtypes and three non-diseased brain samples. We collected FFPE material from the same patients that were included in our previous study (Gravendeel et al. Cancer Res 2009). FFPE expression profiling was performed using Hu_Ex_1.0_st “exon” arrays (Affymetrix) in combination with Nugen WT-Ovation technology (FFPE V2 and Exon modules). FFPE expression profiles were assigned to a molecular cluster based on its nearest centroid using the 20.000 most variably expressed exons. Preliminary analysis indicates that approximately 75% of all samples were assigned to the correct molecular cluster. Survival data confirmed that the molecular clusters identified using FFPE material retained significant prognostic value, similar to those obtained using fresh frozen material (p=0.0016). Our data indicate that exon arrays in combination with Nugen WT technology are a suitable platform to perform expression profiling on FFPE samples. We are currently expanding our dataset to include FFPE samples from a large phase III European trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3936. doi:10.1158/1538-7445.AM2011-3936
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3936
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Abstract 3932: Tetraploid gliomas share molecular features with pilocytic astrocytomas
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3932-3932
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3932-3932
    Abstract: We have performed expression profiling on 276 glioma samples of all histological subtypes, which resulted in the identification of seven distinct molecular subgroups. Interestingly, pilocytic astrocytomas (PAs) (n=6; adults) were assigned to one specific molecular cluster, together with four other, more malignant, gliomas. All the non-PAs were histologically diagnosed as higher grade gliomas with pilocytic features. Interestingly, there was a dramatic difference between survival of PAs and gliomas of other histological subtypes in this molecular cluster ( & gt;10.6 years vs. 3.4 (avg.) years; p = 0.03). Validation with an external dataset containing only PAs (GSE12907) showed that PAs are virtually always assigned to this molecular cluster, confirming the stability of the cluster. However, similar to our dataset, a subset of samples of both the REMBRANDT (8%) and TCGA (1%) datasets was also assigned to this molecular cluster. To further explore the differences between PAs and non-PAs in this molecular cluster, we performed genotyping using SNP 6.0 chip arrays. As reported previously, all PAs have only one larger genetic aberration; a focal amplification on locus 7q34, which is indicative for the presence of the tandem duplication KIAA1549-BRAF. One of the four samples of other histology also had this identical genetic aberration as PAs. The other (3/4) non-PA gliomas showed more genetic aberrations than the PAs. All patients harboring the KIAA1549-BRAF duplication were still alive (“survivors”) at the moment of writing this abstract (survival 10.6-19.6 years), whereas the remaining patients (“non-survivors”) all died within 0.44-2.7 years. High copy EGFR amplification was seen in none of the survivors but all of the other tumors. None of the samples in this cluster showed an IDH1-132H mutation. Closer inspection of the SNP arrays indicated that all non-survivors are tetraploid, whilst tumors of all survivors are near diploid (except for 3n on 7q34). The ploidy of all samples is currently validated using Fluorescence In Situ Hybridization (FISH). Polyploidy was not observed in any of the other molecular clusters. Validation with the REMBRANDT and the TCGA datasets showed that non-PAs assigned to this molecular cluster had a poor survival, similar to the non-PAs in our dataset. Interestingly, tetraploidy and EGFR amplification were also seen in the GBM samples from the TCGA that were assigned to this cluster. Gliomas from other molecular subtypes did not show tetraploidy on SNP chip data. In conclusion, we have discovered and validated a glioma subtype that shares molecular (RNA expression profile) and histological features with PAs. In spite of these similarities (and in contrast to the PAs), such tumors have a relatively poor prognosis. They are characterized by EGFR amplification and a near tetraploid cytogenetic profile. Identification of this specific subtype may have important therapeutic consequences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2011-3932
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3932
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 4170: A transgenic zebrafish model for gliomas with mutations in isocitrate dehydrogenase 1
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4170-4170
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4170-4170
    Abstract: The gene encoding Isocitrate dehydrogenase 1 (IDH1) is frequently mutated in gliomas, chondrosarcomas, acute myeloid leukemia and intrahepatic cholangiocarcinomas. As there are few in-vivo model systems for IDH-mutated tumors we have created a transgenic zebrafish (Danio rerio) model expressing mutant IDH1. We have chosen the zebrafish as a model because they are transparent (allowing monitoring of the transgene in-vivo) and drug screening assays are straightforward (they are simply added to the aquarium). IDH1R132H and IDH1R132C, mutations found in tumors that both produce D-2-hydroxyglutarate (D2HG) instead of alpha ketoglutarate, were cloned into an expression construct that is driven either by the Nestin or GFAP promoter. IDH1G70D (a loss of function mutation), IDH1wildtype and GFP were used as control. All IDH1 constructs were fused to GFP for visualization. These constructs were injected into fertilized zebrafish eggs at the one-cell stage. All of our transgenic zebrafish lines remain healthy and produce offspring. Transgene expression was detected in the mid/hindbrain of the central nervous system by immunohistochemistry, Western blot and RT-QPCR. A significant increase in the level of D2HG was observed in all transgenic lines expressing IDH1R132C or IDH1R132H, but not in any of the lines expressing control constructs (IDH1wildtype, IDH1G70D or GFP). In contrast to reported, we failed to detect any differences in hydroxymethyl cytosine (the first step in DNA-demethylation) and mature collagen IV levels between wildtype and mutant IDH1 transgenic fish. We also performed microinjections on fertilized eggs to screen for early developmental effects of IDH1R132H and IDH1R132C. Despite of the high expression of the transgene, no developmental effects were found. Our observations therefore suggest that elevated levels of D2HG are insufficient to initiate tumorigenesis or other phenotypic effects in our fish. Treatment of the transgenic zebrafish with an IDH1 mutant inhibitor, AGI-5198, resulted in a reduction in the D2HG level in the mutant zebrafish. The L2HG level was not affected by AGI-5198. As no tumors were formed in our transgenic zebrafish lines, we backcrossed them with Tp53 mutant fish. Analysis of these lines is currently being performed. In summary, we have generated a transgenic zebrafish model system that expresses mutated IDH1 that can be used to study effects of mutant IDH1 (or elevated levels of D2HG) in vivo and can be used for drug screening. Citation Format: Ya D. Gao, Maurice de Wit, Eduard A. Struys, Martine L.M. Lamfers, Gajja S. Salomons, Peter A.E. Sillevis Smitt, Pim J. French. A transgenic zebrafish model for gliomas with mutations in isocitrate dehydrogenase 1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4170.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4170
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
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    Abstract 642: A hypermethylated phenotype as predictive marker for response to PCV in anaplastic oligodendrogliomas. A report from EORTC study 26951.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 642-642
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 642-642
    Abstract: Introduction: In 1995 a large European phase III clinical trial (‘EORTC 26951’) was initiated to examine the effects of adjuvant procarbazine, CCNU and vincristine (PCV) chemotherapy in anaplastic oligodendrogliomas (AOD and AOA). This trial showed that the addition of 6 cycles PCV after 59.4 Gy RT increases overall survival (OS) and progression free survival (PFS) in these tumors. However, some patients appeared to benefit more from the addition of PCV treatment than others. In current study, we aimed to identify the patients in this trial that benefit from adjuvant PCV treatment using genome wide methylation profiling. Methods: Methylation profiles of a total of 115 samples were generated, 49 of which were reported previously. Results: Most (59/66) samples were formalin-fixed and embedded in paraffin (FFPE). Our first experiment was therefore aimed at determining the performance of methylation arrays using such tissue. Paired snap frozen (FF)-FFPE sample analysis on six glioma samples demonstrated that the correlation between FF and FFPE samples was high: 0.961±0.023. Between FFPE technical replicates it was 0.987±0.009. These results demonstrate that methylation profiling can be performed on DNA isolated from FFPE samples. We then performed methylation profiling on an additional 66 samples of the EORTC26951 trial (59 FFPE, 7 FF) and combined the data with those of the 49 FF samples previously analyzed. The cohort analyzed for methylation profiling had similar characteristics as the entire EORTC26951 cohort. However, OS within the RT-only treatment arm of included patients was worse compared to OS in patients not included. Univariate analysis indicated that CIMP (CpG island methylator phenotype) status was a favorable prognostic marker for OS with CIMP+ tumors having a more favorable prognosis than CIMP- tumors (median OS 1.05 v. 6.46 years HR 0.225 95% CI [0.138, 0.369], P & lt;0.0001. Multivariate analysis indicates that CIMP status is a prognostic factor for overall survival that is independent of clinical and histological parameters (age, sex, performance score and review diagnosis). IDH1 mutations (39/51), 1p19q LOH (29/63) and MGMT promoter methylation (45/52) were predominantly identified in CIMP+ tumors whereas EGFR amplification was predominantly identified in the CIMP- subtype (20/42, 48%). When stratified for treatment, CIMP+ tumors showed a clear benefit from adjuvant PCV chemotherapy, both for OS and PFS. Median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.36 years respectively (HR: 0.409; 95% CI [0.224,0.746], P=0.0036). There was no such benefit for CIMP- tumors. Conclusion: Our results suggest that CIMP status is predictive for benefit from adjuvant PCV in AODs and AOAs in samples of the EORTC 26951 clinical trial. Further validation of these results is urgently required. Citation Format: Pim J. French, Lale Erdem-Eraslan, Ahmed Idbaih, Wim Spliet, Wilfred den Dunnen, Johannes L. Teepen, Pieter Wesseling, Peter A. Sillevis Smitt, Johan M. Kros, Thierry Gorlia, Martin van den Bent. A hypermethylated phenotype as predictive marker for response to PCV in anaplastic oligodendrogliomas. A report from EORTC study 26951. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2013-642
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-642
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 22 ( 2011-11-15), p. 7148-7155
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 22 ( 2011-11-15), p. 7148-7155
    Abstract: Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas. Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive. Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP−) subgroup (5.62 vs. 1.24 years; P & lt; 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA). Conclusion: The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. Clin Cancer Res; 17(22); 7148–55. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-1274
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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