Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations
Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients h...
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| Veröffentlicht in: | ACTA NEUROPATHOLOGICA 2021-06, Vol.141 (6), p.945-957 |
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| creator | Tesileanu, C. Mircea S Vallentgoed, Wies R Sanson, Marc Taal, Walter Clement, Paul M Wick, Wolfgang Brandes, Alba Ariela Baurain, Jean Francais Chinot, Olivier L Wheeler, Helen Gill, Sanjeev Griffin, Matthew Rogers, Leland Ruda, Roberta Weller, Michael McBain, Catherine Reijneveld, Jaap Enting, Roelien H Caparrotti, Francesca Lesimple, Thierry Clenton, Susan Gijtenbeek, Anja Lim, Elizabeth de Vos, Filip Mulholland, Paul J Taphoorn, Martin J.B de Heer, Iris Hoogstrate, Youri de Wit, Maurice Boggiani, Lorenzo Venneker, Sanne Oosting, Jan Bovee, Judith V.M.G Erridge, Sara Vogelbaum, Michael A Nowak, Anna K Mason, Warren P Kros, Johan M Wesseling, Pieter Aldape, Ken Jenkins, Robert B Dubbink, Hendrikus J Baumert, Brigitta Golfinopoulos, Vassilis Gorlia, Thierry van den Bent, Martin French, Pim J |
| description | Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p |
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Mircea S ; Vallentgoed, Wies R ; Sanson, Marc ; Taal, Walter ; Clement, Paul M ; Wick, Wolfgang ; Brandes, Alba Ariela ; Baurain, Jean Francais ; Chinot, Olivier L ; Wheeler, Helen ; Gill, Sanjeev ; Griffin, Matthew ; Rogers, Leland ; Ruda, Roberta ; Weller, Michael ; McBain, Catherine ; Reijneveld, Jaap ; Enting, Roelien H ; Caparrotti, Francesca ; Lesimple, Thierry ; Clenton, Susan ; Gijtenbeek, Anja ; Lim, Elizabeth ; de Vos, Filip ; Mulholland, Paul J ; Taphoorn, Martin J.B ; de Heer, Iris ; Hoogstrate, Youri ; de Wit, Maurice ; Boggiani, Lorenzo ; Venneker, Sanne ; Oosting, Jan ; Bovee, Judith V.M.G ; Erridge, Sara ; Vogelbaum, Michael A ; Nowak, Anna K ; Mason, Warren P ; Kros, Johan M ; Wesseling, Pieter ; Aldape, Ken ; Jenkins, Robert B ; Dubbink, Hendrikus J ; Baumert, Brigitta ; Golfinopoulos, Vassilis ; Gorlia, Thierry ; van den Bent, Martin ; French, Pim J</creator><creatorcontrib>Tesileanu, C. Mircea S ; Vallentgoed, Wies R ; Sanson, Marc ; Taal, Walter ; Clement, Paul M ; Wick, Wolfgang ; Brandes, Alba Ariela ; Baurain, Jean Francais ; Chinot, Olivier L ; Wheeler, Helen ; Gill, Sanjeev ; Griffin, Matthew ; Rogers, Leland ; Ruda, Roberta ; Weller, Michael ; McBain, Catherine ; Reijneveld, Jaap ; Enting, Roelien H ; Caparrotti, Francesca ; Lesimple, Thierry ; Clenton, Susan ; Gijtenbeek, Anja ; Lim, Elizabeth ; de Vos, Filip ; Mulholland, Paul J ; Taphoorn, Martin J.B ; de Heer, Iris ; Hoogstrate, Youri ; de Wit, Maurice ; Boggiani, Lorenzo ; Venneker, Sanne ; Oosting, Jan ; Bovee, Judith V.M.G ; Erridge, Sara ; Vogelbaum, Michael A ; Nowak, Anna K ; Mason, Warren P ; Kros, Johan M ; Wesseling, Pieter ; Aldape, Ken ; Jenkins, Robert B ; Dubbink, Hendrikus J ; Baumert, Brigitta ; Golfinopoulos, Vassilis ; Gorlia, Thierry ; van den Bent, Martin ; French, Pim J</creatorcontrib><description>Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. 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IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. 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Mircea S</au><au>Vallentgoed, Wies R</au><au>Sanson, Marc</au><au>Taal, Walter</au><au>Clement, Paul M</au><au>Wick, Wolfgang</au><au>Brandes, Alba Ariela</au><au>Baurain, Jean Francais</au><au>Chinot, Olivier L</au><au>Wheeler, Helen</au><au>Gill, Sanjeev</au><au>Griffin, Matthew</au><au>Rogers, Leland</au><au>Ruda, Roberta</au><au>Weller, Michael</au><au>McBain, Catherine</au><au>Reijneveld, Jaap</au><au>Enting, Roelien H</au><au>Caparrotti, Francesca</au><au>Lesimple, Thierry</au><au>Clenton, Susan</au><au>Gijtenbeek, Anja</au><au>Lim, Elizabeth</au><au>de Vos, Filip</au><au>Mulholland, Paul J</au><au>Taphoorn, Martin J.B</au><au>de Heer, Iris</au><au>Hoogstrate, Youri</au><au>de Wit, Maurice</au><au>Boggiani, Lorenzo</au><au>Venneker, Sanne</au><au>Oosting, Jan</au><au>Bovee, Judith V.M.G</au><au>Erridge, Sara</au><au>Vogelbaum, Michael A</au><au>Nowak, Anna K</au><au>Mason, Warren P</au><au>Kros, Johan M</au><au>Wesseling, Pieter</au><au>Aldape, Ken</au><au>Jenkins, Robert B</au><au>Dubbink, Hendrikus J</au><au>Baumert, Brigitta</au><au>Golfinopoulos, Vassilis</au><au>Gorlia, Thierry</au><au>van den Bent, Martin</au><au>French, Pim J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations</atitle><jtitle>ACTA NEUROPATHOLOGICA</jtitle><date>2021-06</date><risdate>2021</risdate><volume>141</volume><issue>6</issue><spage>945</spage><epage>957</epage><pages>945-957</pages><issn>0001-6322</issn><abstract>Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.</abstract><pub>SPRINGER</pub><oa>free_for_read</oa></addata></record> |
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| source | Lirias (KU Leuven Association); SpringerNature Journals |
| title | Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations |
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