Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

Kristian W. Pajtler, Ji Wen, Martin Sill, Tong Lin, Wilda Orisme, Bo Tang, Jens Martin Hübner, Vijay Ramaswamy, Sujuan Jia, James D. Dalton, Kelly Haupfear, Hazel A. Rogers, Chandanamali Punchihewa, Ryan Lee, John Easton, Gang Wu, Timothy A. Ritzmann, Rebecca Chapman, Lukas Chavez, Frederick BoopPaul Klimo, Noah D. Sabin, Robert Ogg, Stephen C. Mack, Brian D. Freibaum, Hong Joo Kim, Hendrik Witt, David T.W. Jones, Baohan Vo, Amar Gajjar, Stan Pounds, Arzu Onar-Thomas, Martine F. Roussel, Jinghui Zhang, J. Paul Taylor, Thomas E. Merchant, Richard Grundy, Ruth G. Tatevossian, Michael D. Taylor, Stefan M. Pfister, Andrey Korshunov, Marcel Kool, David W. Ellison

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)211-226
Number of pages16
JournalActa Neuropathologica
Volume136
Issue number2
DOIs
StatePublished - Aug 1 2018

Fingerprint

Ependymoma
DNA Fingerprinting
DNA Methylation
varespladib methyl
Mutation
Neoplasms
Neural Stem Cells
Gene Expression Profiling
Missense Mutation
Immunoprecipitation
Mass Spectrometry
Biomarkers
Cell Line
Survival

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Pajtler, K. W., Wen, J., Sill, M., Lin, T., Orisme, W., Tang, B., ... Ellison, D. W. (2018). Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathologica, 136(2), 211-226. https://doi.org/10.1007/s00401-018-1877-0

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, Frederick; 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.

In: Acta Neuropathologica, Vol. 136, No. 2, 01.08.2018, p. 211-226.

Research output: Contribution to journalArticle

Pajtler, KW, Wen, J, Sill, M, Lin, T, Orisme, W, Tang, B, Hübner, JM, Ramaswamy, V, Jia, S, Dalton, JD, Haupfear, K, Rogers, HA, Punchihewa, C, Lee, R, Easton, J, Wu, G, Ritzmann, TA, Chapman, R, Chavez, L, Boop, F, Klimo, P, Sabin, ND, Ogg, R, Mack, SC, Freibaum, BD, Kim, HJ, Witt, H, Jones, DTW, Vo, B, Gajjar, A, Pounds, S, Onar-Thomas, A, Roussel, MF, Zhang, J, Taylor, JP, Merchant, TE, Grundy, R, Tatevossian, RG, Taylor, MD, Pfister, SM, Korshunov, A, Kool, M & Ellison, DW 2018, 'Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas', Acta Neuropathologica, vol. 136, no. 2, pp. 211-226. https://doi.org/10.1007/s00401-018-1877-0
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, Frederick ; 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. In: Acta Neuropathologica. 2018 ; Vol. 136, No. 2. pp. 211-226.
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T1 - Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

AU - Pajtler, Kristian W.

AU - Wen, Ji

AU - Sill, Martin

AU - Lin, Tong

AU - Orisme, Wilda

AU - Tang, Bo

AU - Hübner, Jens Martin

AU - Ramaswamy, Vijay

AU - Jia, Sujuan

AU - Dalton, James D.

AU - Haupfear, Kelly

AU - Rogers, Hazel A.

AU - Punchihewa, Chandanamali

AU - Lee, Ryan

AU - Easton, John

AU - Wu, Gang

AU - Ritzmann, Timothy A.

AU - Chapman, Rebecca

AU - Chavez, Lukas

AU - Boop, Frederick

AU - Klimo, Paul

AU - Sabin, Noah D.

AU - Ogg, Robert

AU - Mack, Stephen C.

AU - Freibaum, Brian D.

AU - Kim, Hong Joo

AU - Witt, Hendrik

AU - Jones, David T.W.

AU - Vo, Baohan

AU - Gajjar, Amar

AU - Pounds, Stan

AU - Onar-Thomas, Arzu

AU - Roussel, Martine F.

AU - Zhang, Jinghui

AU - Taylor, J. Paul

AU - Merchant, Thomas E.

AU - Grundy, Richard

AU - Tatevossian, Ruth G.

AU - Taylor, Michael D.

AU - Pfister, Stefan M.

AU - Korshunov, Andrey

AU - Kool, Marcel

AU - Ellison, David W.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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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