Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme
Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggeste...
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| Veröffentlicht in: | BMC cancer 2013-12, Vol.13 (1), p.617-617, Article 617 |
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| creator | Oberstadt, Moritz C Bien-Möller, Sandra Weitmann, Kerstin Herzog, Susann Hentschel, Katharina Rimmbach, Christian Vogelgesang, Silke Balz, Ellen Fink, Matthias Michael, Heike Zeden, Jan-Philip Bruckmüller, Henrike Werk, Anneke N Cascorbi, Ingolf Hoffmann, Wolfgang Rosskopf, Dieter Schroeder, Henry W S Kroemer, Heyo K |
| description | Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.
Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.
Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.
In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival. |
| doi_str_mv | 10.1186/1471-2407-13-617 |
| format | Article |
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Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.
Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.
In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival.</description><identifier>ISSN: 1471-2407</identifier><identifier>EISSN: 1471-2407</identifier><identifier>DOI: 10.1186/1471-2407-13-617</identifier><identifier>PMID: 24380367</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>ABC transporters ; Adult ; Aged ; Analysis ; ATP Binding Cassette Transporter, Sub-Family B ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; Brain Neoplasms - genetics ; Brain Neoplasms - mortality ; Brain Neoplasms - pathology ; Brain Neoplasms - therapy ; Brain tumors ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; DNA Modification Methylases - genetics ; DNA repair ; DNA Repair Enzymes - genetics ; Drug resistance ; Drug Resistance, Neoplasm - genetics ; Drug therapy ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Female ; Gene Expression ; Genes ; Genetic aspects ; Genetic research ; Glioblastoma - genetics ; Glioblastoma - mortality ; Glioblastoma - pathology ; Glioblastoma - therapy ; Glioblastoma multiforme ; Humans ; Male ; Medical prognosis ; Middle Aged ; Neoplasm Proteins - genetics ; Neurosurgery ; Physiological aspects ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Recurrence ; Single nucleotide polymorphisms ; Studies ; Tumor Suppressor Proteins - genetics</subject><ispartof>BMC cancer, 2013-12, Vol.13 (1), p.617-617, Article 617</ispartof><rights>COPYRIGHT 2013 BioMed Central Ltd.</rights><rights>2013 Oberstadt et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2013 Oberstadt et al.; licensee BioMed Central Ltd. 2013 Oberstadt et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b715t-b2de622d9965876921825a2e89effd7e9ca26347c69bf0ebbf662bc154b161333</citedby><cites>FETCH-LOGICAL-b715t-b2de622d9965876921825a2e89effd7e9ca26347c69bf0ebbf662bc154b161333</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890604/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890604/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24380367$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oberstadt, Moritz C</creatorcontrib><creatorcontrib>Bien-Möller, Sandra</creatorcontrib><creatorcontrib>Weitmann, Kerstin</creatorcontrib><creatorcontrib>Herzog, Susann</creatorcontrib><creatorcontrib>Hentschel, Katharina</creatorcontrib><creatorcontrib>Rimmbach, Christian</creatorcontrib><creatorcontrib>Vogelgesang, Silke</creatorcontrib><creatorcontrib>Balz, Ellen</creatorcontrib><creatorcontrib>Fink, Matthias</creatorcontrib><creatorcontrib>Michael, Heike</creatorcontrib><creatorcontrib>Zeden, Jan-Philip</creatorcontrib><creatorcontrib>Bruckmüller, Henrike</creatorcontrib><creatorcontrib>Werk, Anneke N</creatorcontrib><creatorcontrib>Cascorbi, Ingolf</creatorcontrib><creatorcontrib>Hoffmann, Wolfgang</creatorcontrib><creatorcontrib>Rosskopf, Dieter</creatorcontrib><creatorcontrib>Schroeder, Henry W S</creatorcontrib><creatorcontrib>Kroemer, Heyo K</creatorcontrib><title>Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme</title><title>BMC cancer</title><addtitle>BMC Cancer</addtitle><description>Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.
Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.
Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.
In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival.</description><subject>ABC transporters</subject><subject>Adult</subject><subject>Aged</subject><subject>Analysis</subject><subject>ATP Binding Cassette Transporter, Sub-Family B</subject><subject>ATP Binding Cassette Transporter, Sub-Family G, Member 2</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - mortality</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - therapy</subject><subject>Brain tumors</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA Modification Methylases - genetics</subject><subject>DNA repair</subject><subject>DNA Repair Enzymes - genetics</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drug therapy</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma - therapy</subject><subject>Glioblastoma multiforme</subject><subject>Humans</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Middle Aged</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neurosurgery</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Promoter Regions, Genetic</subject><subject>Recurrence</subject><subject>Single nucleotide polymorphisms</subject><subject>Studies</subject><subject>Tumor Suppressor Proteins - 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Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.
Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.
Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.
In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>24380367</pmid><doi>10.1186/1471-2407-13-617</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3890604 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Springer Nature OA Free Journals |
| subjects | ABC transporters Adult Aged Analysis ATP Binding Cassette Transporter, Sub-Family B ATP Binding Cassette Transporter, Sub-Family G, Member 2 ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - genetics Brain Neoplasms - genetics Brain Neoplasms - mortality Brain Neoplasms - pathology Brain Neoplasms - therapy Brain tumors Deoxyribonucleic acid DNA DNA Methylation DNA Modification Methylases - genetics DNA repair DNA Repair Enzymes - genetics Drug resistance Drug Resistance, Neoplasm - genetics Drug therapy Epigenesis, Genetic Epigenetic inheritance Epigenetics Female Gene Expression Genes Genetic aspects Genetic research Glioblastoma - genetics Glioblastoma - mortality Glioblastoma - pathology Glioblastoma - therapy Glioblastoma multiforme Humans Male Medical prognosis Middle Aged Neoplasm Proteins - genetics Neurosurgery Physiological aspects Polymorphism, Single Nucleotide Promoter Regions, Genetic Recurrence Single nucleotide polymorphisms Studies Tumor Suppressor Proteins - genetics |
| title | Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T18%3A58%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Epigenetic%20modulation%20of%20the%20drug%20resistance%20genes%20MGMT,%20ABCB1%20and%20ABCG2%20in%20glioblastoma%20multiforme&rft.jtitle=BMC%20cancer&rft.au=Oberstadt,%20Moritz%20C&rft.date=2013-12-31&rft.volume=13&rft.issue=1&rft.spage=617&rft.epage=617&rft.pages=617-617&rft.artnum=617&rft.issn=1471-2407&rft.eissn=1471-2407&rft_id=info:doi/10.1186/1471-2407-13-617&rft_dat=%3Cgale_pubme%3EA534612314%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1476521611&rft_id=info:pmid/24380367&rft_galeid=A534612314&rfr_iscdi=true |