Telomerase reverse transcriptase promoter mutation– and O6-methylguanine DNA methyltransferase promoter methylation–mediated sensitivity to temozolomide in isocitrate dehydrogenase–wild-type glioblastoma: is there a link?
Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)–wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter–methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TE...
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| Veröffentlicht in: | European journal of cancer (1990) 2021-04, Vol.147, p.84-94 |
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| creator | Gramatzki, Dorothee Felsberg, Jörg Hentschel, Bettina Wolter, Marietta Schackert, Gabriele Westphal, Manfred Regli, Luca Thon, Niklas Tatagiba, Marcos Wick, Wolfgang Schlegel, Uwe Krex, Dietmar Matschke, Jakob Roth, Patrick Suresh, Marian P. Kamp, Marcel A. Rushing, Elisabeth J. Pietsch, Torsten von Deimling, Andreas Sabel, Michael Loeffler, Markus Weller, Michael Reifenberger, Guido |
| description | Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)–wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter–methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.
MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH–wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).
In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter–unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07–2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter–methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.
Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter–methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH–wild-type glioblastoma.
•MGMT and TERT status do not interact prognostically in IDH-wild-type glioblastoma.•TERT mutation is not linked to benefit from TMZ in IDH-wildtype glioblastoma.•C228T and C250T TERT promoter-mutant glioblastoma show similar outcome.•TERT status is not required for prognostic stratification in clinical trials. |
| doi_str_mv | 10.1016/j.ejca.2021.01.014 |
| format | Article |
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MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH–wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).
In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter–unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07–2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter–methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.
Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter–methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH–wild-type glioblastoma.
•MGMT and TERT status do not interact prognostically in IDH-wild-type glioblastoma.•TERT mutation is not linked to benefit from TMZ in IDH-wildtype glioblastoma.•C228T and C250T TERT promoter-mutant glioblastoma show similar outcome.•TERT status is not required for prognostic stratification in clinical trials.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2021.01.014</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Brain cancer ; Chemotherapy ; Confidence intervals ; Dehydrogenase ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA methyltransferase ; Glioblastoma ; Glioma ; IDH ; Isocitrate dehydrogenase ; Methylation ; Methylguanine ; MGMT ; Mutation ; Mutation hot spots ; O6-methylguanine-DNA methyltransferase ; RNA-directed DNA polymerase ; Sensitivity ; Survival ; Telomerase ; Telomerase reverse transcriptase ; Temozolomide ; TERT ; Tumors ; wild-type</subject><ispartof>European journal of cancer (1990), 2021-04, Vol.147, p.84-94</ispartof><rights>2021 The Authors</rights><rights>Copyright Elsevier Science Ltd. Apr 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2504-b8af4f3d0cd0824e39511e02e526e1fb2de1d3d0fe68d62653b2c75408db7273</citedby><cites>FETCH-LOGICAL-c2504-b8af4f3d0cd0824e39511e02e526e1fb2de1d3d0fe68d62653b2c75408db7273</cites><orcidid>0000-0003-4639-4474 ; 0000-0001-9793-363X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejca.2021.01.014$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids></links><search><creatorcontrib>Gramatzki, Dorothee</creatorcontrib><creatorcontrib>Felsberg, Jörg</creatorcontrib><creatorcontrib>Hentschel, Bettina</creatorcontrib><creatorcontrib>Wolter, Marietta</creatorcontrib><creatorcontrib>Schackert, Gabriele</creatorcontrib><creatorcontrib>Westphal, Manfred</creatorcontrib><creatorcontrib>Regli, Luca</creatorcontrib><creatorcontrib>Thon, Niklas</creatorcontrib><creatorcontrib>Tatagiba, Marcos</creatorcontrib><creatorcontrib>Wick, Wolfgang</creatorcontrib><creatorcontrib>Schlegel, Uwe</creatorcontrib><creatorcontrib>Krex, Dietmar</creatorcontrib><creatorcontrib>Matschke, Jakob</creatorcontrib><creatorcontrib>Roth, Patrick</creatorcontrib><creatorcontrib>Suresh, Marian P.</creatorcontrib><creatorcontrib>Kamp, Marcel A.</creatorcontrib><creatorcontrib>Rushing, Elisabeth J.</creatorcontrib><creatorcontrib>Pietsch, Torsten</creatorcontrib><creatorcontrib>von Deimling, Andreas</creatorcontrib><creatorcontrib>Sabel, Michael</creatorcontrib><creatorcontrib>Loeffler, Markus</creatorcontrib><creatorcontrib>Weller, Michael</creatorcontrib><creatorcontrib>Reifenberger, Guido</creatorcontrib><title>Telomerase reverse transcriptase promoter mutation– and O6-methylguanine DNA methyltransferase promoter methylation–mediated sensitivity to temozolomide in isocitrate dehydrogenase–wild-type glioblastoma: is there a link?</title><title>European journal of cancer (1990)</title><description>Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)–wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter–methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.
MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH–wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).
In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter–unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07–2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter–methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.
Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter–methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH–wild-type glioblastoma.
•MGMT and TERT status do not interact prognostically in IDH-wild-type glioblastoma.•TERT mutation is not linked to benefit from TMZ in IDH-wildtype glioblastoma.•C228T and C250T TERT promoter-mutant glioblastoma show similar outcome.•TERT status is not required for prognostic stratification in clinical trials.</description><subject>Brain cancer</subject><subject>Chemotherapy</subject><subject>Confidence intervals</subject><subject>Dehydrogenase</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA methyltransferase</subject><subject>Glioblastoma</subject><subject>Glioma</subject><subject>IDH</subject><subject>Isocitrate dehydrogenase</subject><subject>Methylation</subject><subject>Methylguanine</subject><subject>MGMT</subject><subject>Mutation</subject><subject>Mutation hot spots</subject><subject>O6-methylguanine-DNA methyltransferase</subject><subject>RNA-directed DNA polymerase</subject><subject>Sensitivity</subject><subject>Survival</subject><subject>Telomerase</subject><subject>Telomerase reverse transcriptase</subject><subject>Temozolomide</subject><subject>TERT</subject><subject>Tumors</subject><subject>wild-type</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kcuKFDEUhgtRsB19AVcBN26qTdJJXUSQYbzC4Gx6H1LJqe6UqaRNUj2UK9_BN9QXMTWlCC6EAwfO-f-PcymKpwRvCSbVi2ELg5JbiinZ4iXYvWJDmrotccPp_WKDW96WDWbtw-JRjAPGuG4Y3hQ_92D9CEFGQAHOEHJOQbqogjmlpXoKfvQJAhqnJJPx7se370g6jW6qcoR0nO1hks44QG8-XaK1ckfoV-pf_13rD2IEbWQCjSK4aJI5mzSj5FGC0X_1eSajARmHTPTKZF4CpOE46-AP4DI3I26N1WWaT4AO1vjOypj8KF9mC0pHCIAkssZ9fv24eNBLG-HJ73xR7N-93V99KK9v3n-8urwuFeWYlV0je9bvNFYaN5TBruWEAKbAaQWk76gGonO7h6rRFa34rqOq5gw3uqtpvbsonq_YvPGXCWISo4kKrJUO_BQFZS2jdUtbnKXP_pEOfgouDycop6TihHKeVXRVqeBjDNCLUzCjDLMgWCxvF4NY3i6Wtwu8BMumV6sJ8qZnA0FEZcCpfO4AKgntzf_svwDsCMCu</recordid><startdate>202104</startdate><enddate>202104</enddate><creator>Gramatzki, Dorothee</creator><creator>Felsberg, Jörg</creator><creator>Hentschel, Bettina</creator><creator>Wolter, Marietta</creator><creator>Schackert, Gabriele</creator><creator>Westphal, Manfred</creator><creator>Regli, Luca</creator><creator>Thon, Niklas</creator><creator>Tatagiba, Marcos</creator><creator>Wick, Wolfgang</creator><creator>Schlegel, Uwe</creator><creator>Krex, Dietmar</creator><creator>Matschke, Jakob</creator><creator>Roth, Patrick</creator><creator>Suresh, Marian P.</creator><creator>Kamp, Marcel A.</creator><creator>Rushing, Elisabeth J.</creator><creator>Pietsch, Torsten</creator><creator>von Deimling, Andreas</creator><creator>Sabel, Michael</creator><creator>Loeffler, Markus</creator><creator>Weller, Michael</creator><creator>Reifenberger, Guido</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4639-4474</orcidid><orcidid>https://orcid.org/0000-0001-9793-363X</orcidid></search><sort><creationdate>202104</creationdate><title>Telomerase reverse transcriptase promoter mutation– and O6-methylguanine DNA methyltransferase promoter methylation–mediated sensitivity to temozolomide in isocitrate dehydrogenase–wild-type glioblastoma: is there a link?</title><author>Gramatzki, Dorothee ; Felsberg, Jörg ; Hentschel, Bettina ; Wolter, Marietta ; Schackert, Gabriele ; Westphal, Manfred ; Regli, Luca ; Thon, Niklas ; Tatagiba, Marcos ; Wick, Wolfgang ; Schlegel, Uwe ; Krex, Dietmar ; Matschke, Jakob ; Roth, Patrick ; Suresh, Marian P. ; Kamp, Marcel A. ; Rushing, Elisabeth J. ; Pietsch, Torsten ; von Deimling, Andreas ; Sabel, Michael ; Loeffler, Markus ; Weller, Michael ; Reifenberger, Guido</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2504-b8af4f3d0cd0824e39511e02e526e1fb2de1d3d0fe68d62653b2c75408db7273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Brain cancer</topic><topic>Chemotherapy</topic><topic>Confidence intervals</topic><topic>Dehydrogenase</topic><topic>Dehydrogenases</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA methyltransferase</topic><topic>Glioblastoma</topic><topic>Glioma</topic><topic>IDH</topic><topic>Isocitrate dehydrogenase</topic><topic>Methylation</topic><topic>Methylguanine</topic><topic>MGMT</topic><topic>Mutation</topic><topic>Mutation hot spots</topic><topic>O6-methylguanine-DNA methyltransferase</topic><topic>RNA-directed DNA polymerase</topic><topic>Sensitivity</topic><topic>Survival</topic><topic>Telomerase</topic><topic>Telomerase reverse transcriptase</topic><topic>Temozolomide</topic><topic>TERT</topic><topic>Tumors</topic><topic>wild-type</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gramatzki, Dorothee</creatorcontrib><creatorcontrib>Felsberg, Jörg</creatorcontrib><creatorcontrib>Hentschel, Bettina</creatorcontrib><creatorcontrib>Wolter, Marietta</creatorcontrib><creatorcontrib>Schackert, Gabriele</creatorcontrib><creatorcontrib>Westphal, Manfred</creatorcontrib><creatorcontrib>Regli, Luca</creatorcontrib><creatorcontrib>Thon, Niklas</creatorcontrib><creatorcontrib>Tatagiba, Marcos</creatorcontrib><creatorcontrib>Wick, Wolfgang</creatorcontrib><creatorcontrib>Schlegel, Uwe</creatorcontrib><creatorcontrib>Krex, Dietmar</creatorcontrib><creatorcontrib>Matschke, Jakob</creatorcontrib><creatorcontrib>Roth, Patrick</creatorcontrib><creatorcontrib>Suresh, Marian P.</creatorcontrib><creatorcontrib>Kamp, Marcel A.</creatorcontrib><creatorcontrib>Rushing, Elisabeth J.</creatorcontrib><creatorcontrib>Pietsch, Torsten</creatorcontrib><creatorcontrib>von Deimling, Andreas</creatorcontrib><creatorcontrib>Sabel, Michael</creatorcontrib><creatorcontrib>Loeffler, Markus</creatorcontrib><creatorcontrib>Weller, Michael</creatorcontrib><creatorcontrib>Reifenberger, Guido</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gramatzki, Dorothee</au><au>Felsberg, Jörg</au><au>Hentschel, Bettina</au><au>Wolter, Marietta</au><au>Schackert, Gabriele</au><au>Westphal, Manfred</au><au>Regli, Luca</au><au>Thon, Niklas</au><au>Tatagiba, Marcos</au><au>Wick, Wolfgang</au><au>Schlegel, Uwe</au><au>Krex, Dietmar</au><au>Matschke, Jakob</au><au>Roth, Patrick</au><au>Suresh, Marian P.</au><au>Kamp, Marcel A.</au><au>Rushing, Elisabeth J.</au><au>Pietsch, Torsten</au><au>von Deimling, Andreas</au><au>Sabel, Michael</au><au>Loeffler, Markus</au><au>Weller, Michael</au><au>Reifenberger, Guido</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Telomerase reverse transcriptase promoter mutation– and O6-methylguanine DNA methyltransferase promoter methylation–mediated sensitivity to temozolomide in isocitrate dehydrogenase–wild-type glioblastoma: is there a link?</atitle><jtitle>European journal of cancer (1990)</jtitle><date>2021-04</date><risdate>2021</risdate><volume>147</volume><spage>84</spage><epage>94</epage><pages>84-94</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)–wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter–methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.
MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH–wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).
In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter–unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07–2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter–methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.
Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter–methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH–wild-type glioblastoma.
•MGMT and TERT status do not interact prognostically in IDH-wild-type glioblastoma.•TERT mutation is not linked to benefit from TMZ in IDH-wildtype glioblastoma.•C228T and C250T TERT promoter-mutant glioblastoma show similar outcome.•TERT status is not required for prognostic stratification in clinical trials.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><doi>10.1016/j.ejca.2021.01.014</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4639-4474</orcidid><orcidid>https://orcid.org/0000-0001-9793-363X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Brain cancer Chemotherapy Confidence intervals Dehydrogenase Dehydrogenases Deoxyribonucleic acid DNA DNA methylation DNA methyltransferase Glioblastoma Glioma IDH Isocitrate dehydrogenase Methylation Methylguanine MGMT Mutation Mutation hot spots O6-methylguanine-DNA methyltransferase RNA-directed DNA polymerase Sensitivity Survival Telomerase Telomerase reverse transcriptase Temozolomide TERT Tumors wild-type |
| title | Telomerase reverse transcriptase promoter mutation– and O6-methylguanine DNA methyltransferase promoter methylation–mediated sensitivity to temozolomide in isocitrate dehydrogenase–wild-type glioblastoma: is there a link? |
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