Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas
Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were d...
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Springer Nature
2018
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| author | Pajtler, Kristian W. Wen, Ji Sill, Martin Lin, Tong Orisme, Wilda Tang, Bo Hübner, Jens-Martin Ramaswamy, Vijay Jia, Sujuan Dalton, James D. Haupfear, Kelly Rogers, Hazel A. Punchihewa, Chandanamali Lee, Ryan Easton, John Wu, Gang Ritzmann, Timothy A. Chapman, Rebecca Chavez, Lukas Boop, Fredrick A. Klimo, Paul Sabin, Noah D. Ogg, Robert Mack, Stephen C. Freibaum, Brian D. Kim, Hong Joo Witt, Hendrik Jones, David T. W. Vo, Baohan Gajjar, Amar Pounds, Stan Onar-Thomas, Arzu Roussel, Martine F. Zhang, Jinghui Taylor, J. Paul Merchant, Thomas E. Grundy, Richard Tatevossian, Ruth G. Taylor, Michael D. Pfister, Stefan M. Korshunov, Andrey Kool, Marcel Ellison, David W. |
| author_facet | Pajtler, Kristian W. Wen, Ji Sill, Martin Lin, Tong Orisme, Wilda Tang, Bo Hübner, Jens-Martin Ramaswamy, Vijay Jia, Sujuan Dalton, James D. Haupfear, Kelly Rogers, Hazel A. Punchihewa, Chandanamali Lee, Ryan Easton, John Wu, Gang Ritzmann, Timothy A. Chapman, Rebecca Chavez, Lukas Boop, Fredrick A. Klimo, Paul Sabin, Noah D. Ogg, Robert Mack, Stephen C. Freibaum, Brian D. Kim, Hong Joo Witt, Hendrik Jones, David T. W. Vo, Baohan Gajjar, Amar Pounds, Stan Onar-Thomas, Arzu Roussel, Martine F. Zhang, Jinghui Taylor, J. Paul Merchant, Thomas E. Grundy, Richard Tatevossian, Ruth G. Taylor, Michael D. Pfister, Stefan M. Korshunov, Andrey Kool, Marcel Ellison, David W. |
| author_sort | Pajtler, Kristian W. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors. |
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| id | nottingham-54433 |
| institution | University of Nottingham Malaysia Campus |
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| language | English |
| last_indexed | 2025-11-14T20:29:28Z |
| publishDate | 2018 |
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| spelling | nottingham-544332019-06-16T04:30:10Z https://eprints.nottingham.ac.uk/54433/ Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas Pajtler, Kristian W. Wen, Ji Sill, Martin Lin, Tong Orisme, Wilda Tang, Bo Hübner, Jens-Martin Ramaswamy, Vijay Jia, Sujuan Dalton, James D. Haupfear, Kelly Rogers, Hazel A. Punchihewa, Chandanamali Lee, Ryan Easton, John Wu, Gang Ritzmann, Timothy A. Chapman, Rebecca Chavez, Lukas Boop, Fredrick A. Klimo, Paul Sabin, Noah D. Ogg, Robert Mack, Stephen C. Freibaum, Brian D. Kim, Hong Joo Witt, Hendrik Jones, David T. W. Vo, Baohan Gajjar, Amar Pounds, Stan Onar-Thomas, Arzu Roussel, Martine F. Zhang, Jinghui Taylor, J. Paul Merchant, Thomas E. Grundy, Richard Tatevossian, Ruth G. Taylor, Michael D. Pfister, Stefan M. Korshunov, Andrey Kool, Marcel Ellison, David W. Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors. Springer Nature 2018-08-31 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/54433/1/Molecular%20ANEU-D-18-00393_R1_Nottingham.pdf Pajtler, Kristian W., Wen, Ji, Sill, Martin, Lin, Tong, Orisme, Wilda, Tang, Bo, Hübner, Jens-Martin, Ramaswamy, Vijay, Jia, Sujuan, Dalton, James D., Haupfear, Kelly, Rogers, Hazel A., Punchihewa, Chandanamali, Lee, Ryan, Easton, John, Wu, Gang, Ritzmann, Timothy A., Chapman, Rebecca, Chavez, Lukas, Boop, Fredrick A., Klimo, Paul, Sabin, Noah D., Ogg, Robert, Mack, Stephen C., Freibaum, Brian D., Kim, Hong Joo, Witt, Hendrik, Jones, David T. W., Vo, Baohan, Gajjar, Amar, Pounds, Stan, Onar-Thomas, Arzu, Roussel, Martine F., Zhang, Jinghui, Taylor, J. Paul, Merchant, Thomas E., Grundy, Richard, Tatevossian, Ruth G., Taylor, Michael D., Pfister, Stefan M., Korshunov, Andrey, Kool, Marcel and Ellison, David W. (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathologica, 136 (2). pp. 211-226. ISSN 0001-6322 Ependymoma; Molecular heterogeneity; DNA methylation profiling; CXorf67; PRC2; H3 K27M H3 K27-trimethylation https://link.springer.com/article/10.1007%2Fs00401-018-1877-0 doi:10.1007/s00401-018-1877-0 doi:10.1007/s00401-018-1877-0 |
| spellingShingle | Ependymoma; Molecular heterogeneity; DNA methylation profiling; CXorf67; PRC2; H3 K27M H3 K27-trimethylation Pajtler, Kristian W. Wen, Ji Sill, Martin Lin, Tong Orisme, Wilda Tang, Bo Hübner, Jens-Martin Ramaswamy, Vijay Jia, Sujuan Dalton, James D. Haupfear, Kelly Rogers, Hazel A. Punchihewa, Chandanamali Lee, Ryan Easton, John Wu, Gang Ritzmann, Timothy A. Chapman, Rebecca Chavez, Lukas Boop, Fredrick A. Klimo, Paul Sabin, Noah D. Ogg, Robert Mack, Stephen C. Freibaum, Brian D. Kim, Hong Joo Witt, Hendrik Jones, David T. W. Vo, Baohan Gajjar, Amar Pounds, Stan Onar-Thomas, Arzu Roussel, Martine F. Zhang, Jinghui Taylor, J. Paul Merchant, Thomas E. Grundy, Richard Tatevossian, Ruth G. Taylor, Michael D. Pfister, Stefan M. Korshunov, Andrey Kool, Marcel Ellison, David W. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title_full | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title_fullStr | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title_full_unstemmed | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title_short | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas |
| title_sort | molecular heterogeneity and cxorf67 alterations in posterior fossa group a (pfa) ependymomas |
| topic | Ependymoma; Molecular heterogeneity; DNA methylation profiling; CXorf67; PRC2; H3 K27M H3 K27-trimethylation |
| url | https://eprints.nottingham.ac.uk/54433/ https://eprints.nottingham.ac.uk/54433/ https://eprints.nottingham.ac.uk/54433/ |