Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

Matthew Clarke; Alan Mackay; Britta Ismer; Jessica C. Pickles; Ruth G. Tatevossian; Scott Newman; Tejus A. Bale; Iris Stoler; Elisa Izquierdo; Sara Temelso; Diana M. Carvalho; Valeria Molinari; Anna Burford; Louise Howell; Alex Virasami; Amy R. Fairchild; Aimee Avery; Jane Chalker; Mark Kristiansen; Kelly Haupfear; James D. Dalton; Wilda Orisme; Ji Wen; Michael Hubank; Kathreena M. Kurian; Catherine Rowe; Mellissa Maybury; Stephen Crosier; Jeffrey Knipstein; Ulrich Schüller; Uwe Kordes; David E. Kram; Matija Snuderl; Leslie Bridges; Andrew J. Martin; Lawrence J. Doey; Safa Al-Sarraj; Christopher Chandler; Bassel Zebian; Claire Cairns; Rachael Natrajan; Jessica K.R. Boult; Simon P. Robinson; Martin Sill; Ira J. Dunkel; Stephen W. Gilheeney; Marc K. Rosenblum; Debbie Hughes; Paula Z. Proszek; Tobey J. Macdonald; Matthias Preusser; Christine Haberler; Irene Slavc; Roger Packer; Ho Keung Ng; Shani Caspi; Mara Popović; Barbara Faganel Kotnik; Matthew D. Wood; Lissa Baird; Monika Ashok Davare; David A. Solomon; Thale Kristin Olsen; Petter Brandal; Michael Farrell; Jane B. Cryan; Michael Capra; Michael Karremann; Jens Schittenhelm; Martin U. Schuhmann; Martin Ebinger; Winand N.M. Dinjens; Kornelius Kerl; Simone Hettmer; Torsten Pietsch; Felipe Andreiuolo; Pablo Hernáiz Driever; Andrey Korshunov; Lotte Hiddingh; Barbara C. Worst; Dominik Sturm; Marc Zuckermann; Olaf Witt; Tabitha Bloom; Clare Mitchell; Evelina Miele; Giovanna Stefania Colafati; Francesca Diomedi-Camassei; Simon Bailey; Andrew S. Moore; Timothy E.G. Hassall; Stephen P. Lowis; Maria Tsoli; Mark J. Cowley; David S. Ziegler; Matthias A. Karajannis; Kristian Aquilina; Darren R. Hargrave; Fernando Carceller; Lynley V. Marshall; Andreas von Deimling; Christof M. Kramm; Stefan M. Pfister; Felix Sahm; Suzanne J. Baker; Angela Mastronuzzi; Andrea Carai; Maria Vinci; David Capper; Sergey Popov; David W. Ellison; Thomas S. Jacques; David T.W. Jones; Chris Jones

doi:10.1158/2159-8290.CD-19-1030

Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

Matthew Clarke, Alan Mackay, Britta Ismer, Jessica C. Pickles, Ruth G. Tatevossian, Scott Newman, Tejus A. Bale, Iris Stoler, Elisa Izquierdo, Sara Temelso, Diana M. Carvalho, Valeria Molinari, Anna Burford, Louise Howell, Alex Virasami, Amy R. Fairchild, Aimee Avery, Jane Chalker, Mark Kristiansen, Kelly HaupfearJames D. Dalton, Wilda Orisme, Ji Wen, Michael Hubank, Kathreena M. Kurian, Catherine Rowe, Mellissa Maybury, Stephen Crosier, Jeffrey Knipstein, Ulrich Schüller, Uwe Kordes, David E. Kram, Matija Snuderl, Leslie Bridges, Andrew J. Martin, Lawrence J. Doey, Safa Al-Sarraj, Christopher Chandler, Bassel Zebian, Claire Cairns, Rachael Natrajan, Jessica K.R. Boult, Simon P. Robinson, Martin Sill, Ira J. Dunkel, Stephen W. Gilheeney, Marc K. Rosenblum, Debbie Hughes, Paula Z. Proszek, Tobey J. Macdonald, Matthias Preusser, Christine Haberler, Irene Slavc, Roger Packer, Ho Keung Ng, Shani Caspi, Mara Popović, Barbara Faganel Kotnik, Matthew D. Wood, Lissa Baird, Monika Ashok Davare, David A. Solomon, Thale Kristin Olsen, Petter Brandal, Michael Farrell, Jane B. Cryan, Michael Capra, Michael Karremann, Jens Schittenhelm, Martin U. Schuhmann, Martin Ebinger, Winand N.M. Dinjens, Kornelius Kerl, Simone Hettmer, Torsten Pietsch, Felipe Andreiuolo, Pablo Hernáiz Driever, Andrey Korshunov, Lotte Hiddingh, Barbara C. Worst, Dominik Sturm, Marc Zuckermann, Olaf Witt, Tabitha Bloom, Clare Mitchell, Evelina Miele, Giovanna Stefania Colafati, Francesca Diomedi-Camassei, Simon Bailey, Andrew S. Moore, Timothy E.G. Hassall, Stephen P. Lowis, Maria Tsoli, Mark J. Cowley, David S. Ziegler, Matthias A. Karajannis, Kristian Aquilina, Darren R. Hargrave, Fernando Carceller, Lynley V. Marshall, Andreas von Deimling, Christof M. Kramm, Stefan M. Pfister, Felix Sahm, Suzanne J. Baker, Angela Mastronuzzi, Andrea Carai, Maria Vinci, David Capper, Sergey Popov, David W. Ellison, Thomas S. Jacques, David T.W. Jones, Chris Jones

Research output: Contribution to journal › Article › peer-review

121 Scopus citations

Abstract

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrin-sic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.

Original language	English (US)
Pages (from-to)	942-963
Number of pages	22
Journal	Cancer discovery
Volume	10
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-19-1030
State	Published - Jul 2020

ASJC Scopus subject areas

Oncology

Access to Document

10.1158/2159-8290.CD-19-1030

Cite this

Clarke, M., Mackay, A., Ismer, B., Pickles, J. C., Tatevossian, R. G., Newman, S., Bale, T. A., Stoler, I., Izquierdo, E., Temelso, S., Carvalho, D. M., Molinari, V., Burford, A., Howell, L., Virasami, A., Fairchild, A. R., Avery, A., Chalker, J., Kristiansen, M., ... Jones, C. (2020). Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer discovery, 10(7), 942-963. https://doi.org/10.1158/2159-8290.CD-19-1030

Clarke, M, Mackay, A, Ismer, B, Pickles, JC, Tatevossian, RG, Newman, S, Bale, TA, Stoler, I, Izquierdo, E, Temelso, S, Carvalho, DM, Molinari, V, Burford, A, Howell, L, Virasami, A, Fairchild, AR, Avery, A, Chalker, J, Kristiansen, M, Haupfear, K, Dalton, JD, Orisme, W, Wen, J, Hubank, M, Kurian, KM, Rowe, C, Maybury, M, Crosier, S, Knipstein, J, Schüller, U, Kordes, U, Kram, DE, Snuderl, M, Bridges, L, Martin, AJ, Doey, LJ, Al-Sarraj, S, Chandler, C, Zebian, B, Cairns, C, Natrajan, R, Boult, JKR, Robinson, SP, Sill, M, Dunkel, IJ, Gilheeney, SW, Rosenblum, MK, Hughes, D, Proszek, PZ, Macdonald, TJ, Preusser, M, Haberler, C, Slavc, I, Packer, R, Ng, HK, Caspi, S, Popović, M, Kotnik, BF, Wood, MD, Baird, L, Davare, MA, Solomon, DA, Olsen, TK, Brandal, P, Farrell, M, Cryan, JB, Capra, M, Karremann, M, Schittenhelm, J, Schuhmann, MU, Ebinger, M, Dinjens, WNM, Kerl, K, Hettmer, S, Pietsch, T, Andreiuolo, F, Driever, PH, Korshunov, A, Hiddingh, L, Worst, BC, Sturm, D, Zuckermann, M, Witt, O, Bloom, T, Mitchell, C, Miele, E, Colafati, GS, Diomedi-Camassei, F, Bailey, S, Moore, AS, Hassall, TEG, Lowis, SP, Tsoli, M, Cowley, MJ, Ziegler, DS, Karajannis, MA, Aquilina, K, Hargrave, DR, Carceller, F, Marshall, LV, Deimling, AV, Kramm, CM, Pfister, SM, Sahm, F, Baker, SJ, Mastronuzzi, A, Carai, A, Vinci, M, Capper, D, Popov, S, Ellison, DW, Jacques, TS, Jones, DTW & Jones, C 2020, 'Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes', Cancer discovery, vol. 10, no. 7, pp. 942-963. https://doi.org/10.1158/2159-8290.CD-19-1030

@article{1acf24cb7ad84f12bdcf0a62c75092a7,

title = "Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes",

abstract = "Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrin-sic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.",

author = "Matthew Clarke and Alan Mackay and Britta Ismer and Pickles, {Jessica C.} and Tatevossian, {Ruth G.} and Scott Newman and Bale, {Tejus A.} and Iris Stoler and Elisa Izquierdo and Sara Temelso and Carvalho, {Diana M.} and Valeria Molinari and Anna Burford and Louise Howell and Alex Virasami and Fairchild, {Amy R.} and Aimee Avery and Jane Chalker and Mark Kristiansen and Kelly Haupfear and Dalton, {James D.} and Wilda Orisme and Ji Wen and Michael Hubank and Kurian, {Kathreena M.} and Catherine Rowe and Mellissa Maybury and Stephen Crosier and Jeffrey Knipstein and Ulrich Sch{\"u}ller and Uwe Kordes and Kram, {David E.} and Matija Snuderl and Leslie Bridges and Martin, {Andrew J.} and Doey, {Lawrence J.} and Safa Al-Sarraj and Christopher Chandler and Bassel Zebian and Claire Cairns and Rachael Natrajan and Boult, {Jessica K.R.} and Robinson, {Simon P.} and Martin Sill and Dunkel, {Ira J.} and Gilheeney, {Stephen W.} and Rosenblum, {Marc K.} and Debbie Hughes and Proszek, {Paula Z.} and Macdonald, {Tobey J.} and Matthias Preusser and Christine Haberler and Irene Slavc and Roger Packer and Ng, {Ho Keung} and Shani Caspi and Mara Popovi{\'c} and Kotnik, {Barbara Faganel} and Wood, {Matthew D.} and Lissa Baird and Davare, {Monika Ashok} and Solomon, {David A.} and Olsen, {Thale Kristin} and Petter Brandal and Michael Farrell and Cryan, {Jane B.} and Michael Capra and Michael Karremann and Jens Schittenhelm and Schuhmann, {Martin U.} and Martin Ebinger and Dinjens, {Winand N.M.} and Kornelius Kerl and Simone Hettmer and Torsten Pietsch and Felipe Andreiuolo and Driever, {Pablo Hern{\'a}iz} and Andrey Korshunov and Lotte Hiddingh and Worst, {Barbara C.} and Dominik Sturm and Marc Zuckermann and Olaf Witt and Tabitha Bloom and Clare Mitchell and Evelina Miele and Colafati, {Giovanna Stefania} and Francesca Diomedi-Camassei and Simon Bailey and Moore, {Andrew S.} and Hassall, {Timothy E.G.} and Lowis, {Stephen P.} and Maria Tsoli and Cowley, {Mark J.} and Ziegler, {David S.} and Karajannis, {Matthias A.} and Kristian Aquilina and Hargrave, {Darren R.} and Fernando Carceller and Marshall, {Lynley V.} and Deimling, {Andreas von} and Kramm, {Christof M.} and Pfister, {Stefan M.} and Felix Sahm and Baker, {Suzanne J.} and Angela Mastronuzzi and Andrea Carai and Maria Vinci and David Capper and Sergey Popov and Ellison, {David W.} and Jacques, {Thomas S.} and Jones, {David T.W.} and Chris Jones",

note = "Funding Information: This work was supported by the CRIS Cancer Foundation and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Children{\textquoteright}s Charity, and Children with Cancer UK, Cancer Research UK. The authors acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the ICR, the NIHR Great Ormond Street Hospital Biomedical Research Centre, research nurse funding by the Experimental Cancer Medicines Centre (ECMC) Paediatric Network, as well as CRUK support to the Cancer Imaging Centre at the ICR and Royal Marsden in association with the MRC and Department of Health (England; C1060/A16464). Further funding support was provided by the German Children{\textquoteright}s Cancer Foundation (DKKS, project “MNP2.0 – Improving the Diagnostic Accuracy of Pediatric Brain Tumors,” and support for the German Brain Tumor Reference Center of the DGNN, grant 2014.17) and the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grant #01KU1201A), and the DKFZ-MOST Cooperation Program. We would like to thank Laura von Soosten (DKFZ) for technical assistance and Richard Buus (ICR) and the Breast Cancer Now NanoString facility for conducting the NanoString gene expression profiling. The authors thank Brain UK for provision of cases and clinical information. The authors thank the Cure Brain Cancer Foundation, Australian Lions Childhood Cancer Research Foundation, and Lions Club International Foundation (LCIF). Some of the results are in part based upon data generated by Lions Kids Cancer Genome Project (LKCGP) Partners. The authors thank the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility and the Hartwell Center at St. Jude Children{\textquoteright}s Research Hospital for technical support. The authors acknowledge funding from the American, Lebanese and Syrian-Associated Charities (ALSAC). The Queensland Children{\textquoteright}s Tumour Bank is funded by the Children{\textquoteright}s Hospital Foundation (Queensland). This work was funded in part by the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748. We gratefully acknowledge the members of the Memorial Sloan Kettering Molecular Diagnostics Service in the Department of Pathology. M. Snuderl acknowledges funding from the Friedberg Charitable Foundation, the Making Headway Foundation, and the Sohn Conference Foundation. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Vinci is a CwCUK Fellow (grant number 16-234). S.J. Baker acknowledges funding support from the NIH (CA096832). Funding Information: D.S. Ziegler has received speakers bureau honoraria from Bayer. M.A. Karajannis is a consultant/advisory board member at CereXis, Recursion Pharmaceuticals, and Bayer. D.R. Hargrave is a consultant for entrectinib and is a consultant/advisory board member for larotrectinib. L.V. Marshall has received speakers{\textquoteright} bureau honoraria from Bayer. A. von Deimling has received royalties for antibodies for clone H09 from Dianova (IDH1R132H) and for clone VE1 from Roche/Ventana (BRAFV600E). C.M. Kramm reports receiving a commercial research grant from Novartis and is a consultant/advisory board member for Novartis and Boehringer Ingelheim. F. Sahm has received speakers bureau honoraria from Illumina, Agilent, and Medac. D. Capper has ownership interest in a patent pending on DNA methylation–based tumor classification. No potential conflicts of interest were disclosed by the other authors. Funding Information: This work was supported by the CRIS Cancer Foundation and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Children{\textquoteright}s Charity, and Children with Cancer UK, Cancer Research UK. The authors acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the ICR, the NIHR Great Ormond Street Hospital Biomedical Research Centre, research nurse funding by the Experimental Cancer Medicines Centre (ECMC) Paediatric Net-work, as well as CRUK support to the Cancer Imaging Centre at the ICR and Royal Marsden in association with the MRC and Department of Health (England; C1060/A16464). Further funding support was provided by the German Children{\textquoteright}s Cancer Foundation (DKKS, project “MNP2.0 – Improving the Diagnostic Accuracy of Pediatric Brain Tumors,” and support for the German Brain Tumor Reference Center of the DGNN, grant 2014.17) and the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grant #01KU1201A), and the DKFZ-MOST Cooperation Program. We would like to thank Laura von Soosten (DKFZ) for technical assistance and Richard Buus (ICR) and the Breast Cancer Now NanoString facility for conducting the NanoString gene expression profiling. The authors thank Brain UK for provision of cases and clinical information. The authors thank the Cure Brain Cancer Foundation, Australian Lions Childhood Cancer Research Foundation, and Lions Club International Foundation (LCIF). Some of the results are in part based upon data generated by Lions Kids Cancer Genome Project (LKCGP) Partners. The authors thank the German Cancer Research Center (DKFZ) Genomics and Prot-eomics Core Facility and the Hartwell Center at St. Jude Children{\textquoteright}s Research Hospital for technical support. The authors acknowledge funding from the American, Lebanese and Syrian-Associated Chari-ties (ALSAC). The Queensland Children{\textquoteright}s Tumour Bank is funded by the Children{\textquoteright}s Hospital Foundation (Queensland). This work was funded in part by the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748. We gratefully acknowledge the members of the Memorial Sloan Kettering Molecular Diagnostics Service in the Department of Pathology. M. Snuderl acknowledges funding from the Friedberg Charitable Foundation, the Making Headway Foundation, and the Sohn Conference Foun-dation. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Vinci is a CwCUK Fellow (grant number 16-234). S.J. Baker acknowledges funding support from the NIH (CA096832). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = jul,

doi = "10.1158/2159-8290.CD-19-1030",

language = "English (US)",

volume = "10",

pages = "942--963",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

TY - JOUR

T1 - Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

AU - Clarke, Matthew

AU - Mackay, Alan

AU - Ismer, Britta

AU - Pickles, Jessica C.

AU - Tatevossian, Ruth G.

AU - Newman, Scott

AU - Bale, Tejus A.

AU - Stoler, Iris

AU - Izquierdo, Elisa

AU - Temelso, Sara

AU - Carvalho, Diana M.

AU - Molinari, Valeria

AU - Burford, Anna

AU - Howell, Louise

AU - Virasami, Alex

AU - Fairchild, Amy R.

AU - Avery, Aimee

AU - Chalker, Jane

AU - Kristiansen, Mark

AU - Haupfear, Kelly

AU - Dalton, James D.

AU - Orisme, Wilda

AU - Wen, Ji

AU - Hubank, Michael

AU - Kurian, Kathreena M.

AU - Rowe, Catherine

AU - Maybury, Mellissa

AU - Crosier, Stephen

AU - Knipstein, Jeffrey

AU - Schüller, Ulrich

AU - Kordes, Uwe

AU - Kram, David E.

AU - Snuderl, Matija

AU - Bridges, Leslie

AU - Martin, Andrew J.

AU - Doey, Lawrence J.

AU - Al-Sarraj, Safa

AU - Chandler, Christopher

AU - Zebian, Bassel

AU - Cairns, Claire

AU - Natrajan, Rachael

AU - Boult, Jessica K.R.

AU - Robinson, Simon P.

AU - Sill, Martin

AU - Dunkel, Ira J.

AU - Gilheeney, Stephen W.

AU - Rosenblum, Marc K.

AU - Hughes, Debbie

AU - Proszek, Paula Z.

AU - Macdonald, Tobey J.

AU - Preusser, Matthias

AU - Haberler, Christine

AU - Slavc, Irene

AU - Packer, Roger

AU - Ng, Ho Keung

AU - Caspi, Shani

AU - Popović, Mara

AU - Kotnik, Barbara Faganel

AU - Wood, Matthew D.

AU - Baird, Lissa

AU - Davare, Monika Ashok

AU - Solomon, David A.

AU - Olsen, Thale Kristin

AU - Brandal, Petter

AU - Farrell, Michael

AU - Cryan, Jane B.

AU - Capra, Michael

AU - Karremann, Michael

AU - Schittenhelm, Jens

AU - Schuhmann, Martin U.

AU - Ebinger, Martin

AU - Dinjens, Winand N.M.

AU - Kerl, Kornelius

AU - Hettmer, Simone

AU - Pietsch, Torsten

AU - Andreiuolo, Felipe

AU - Driever, Pablo Hernáiz

AU - Korshunov, Andrey

AU - Hiddingh, Lotte

AU - Worst, Barbara C.

AU - Sturm, Dominik

AU - Zuckermann, Marc

AU - Witt, Olaf

AU - Bloom, Tabitha

AU - Mitchell, Clare

AU - Miele, Evelina

AU - Colafati, Giovanna Stefania

AU - Diomedi-Camassei, Francesca

AU - Bailey, Simon

AU - Moore, Andrew S.

AU - Hassall, Timothy E.G.

AU - Lowis, Stephen P.

AU - Tsoli, Maria

AU - Cowley, Mark J.

AU - Ziegler, David S.

AU - Karajannis, Matthias A.

AU - Aquilina, Kristian

AU - Hargrave, Darren R.

AU - Carceller, Fernando

AU - Marshall, Lynley V.

AU - Deimling, Andreas von

AU - Kramm, Christof M.

AU - Pfister, Stefan M.

AU - Sahm, Felix

AU - Baker, Suzanne J.

AU - Mastronuzzi, Angela

AU - Carai, Andrea

AU - Vinci, Maria

AU - Capper, David

AU - Popov, Sergey

AU - Ellison, David W.

AU - Jacques, Thomas S.

AU - Jones, David T.W.

AU - Jones, Chris

N1 - Funding Information: This work was supported by the CRIS Cancer Foundation and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Children’s Charity, and Children with Cancer UK, Cancer Research UK. The authors acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the ICR, the NIHR Great Ormond Street Hospital Biomedical Research Centre, research nurse funding by the Experimental Cancer Medicines Centre (ECMC) Paediatric Network, as well as CRUK support to the Cancer Imaging Centre at the ICR and Royal Marsden in association with the MRC and Department of Health (England; C1060/A16464). Further funding support was provided by the German Children’s Cancer Foundation (DKKS, project “MNP2.0 – Improving the Diagnostic Accuracy of Pediatric Brain Tumors,” and support for the German Brain Tumor Reference Center of the DGNN, grant 2014.17) and the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grant #01KU1201A), and the DKFZ-MOST Cooperation Program. We would like to thank Laura von Soosten (DKFZ) for technical assistance and Richard Buus (ICR) and the Breast Cancer Now NanoString facility for conducting the NanoString gene expression profiling. The authors thank Brain UK for provision of cases and clinical information. The authors thank the Cure Brain Cancer Foundation, Australian Lions Childhood Cancer Research Foundation, and Lions Club International Foundation (LCIF). Some of the results are in part based upon data generated by Lions Kids Cancer Genome Project (LKCGP) Partners. The authors thank the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility and the Hartwell Center at St. Jude Children’s Research Hospital for technical support. The authors acknowledge funding from the American, Lebanese and Syrian-Associated Charities (ALSAC). The Queensland Children’s Tumour Bank is funded by the Children’s Hospital Foundation (Queensland). This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748. We gratefully acknowledge the members of the Memorial Sloan Kettering Molecular Diagnostics Service in the Department of Pathology. M. Snuderl acknowledges funding from the Friedberg Charitable Foundation, the Making Headway Foundation, and the Sohn Conference Foundation. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Vinci is a CwCUK Fellow (grant number 16-234). S.J. Baker acknowledges funding support from the NIH (CA096832). Funding Information: D.S. Ziegler has received speakers bureau honoraria from Bayer. M.A. Karajannis is a consultant/advisory board member at CereXis, Recursion Pharmaceuticals, and Bayer. D.R. Hargrave is a consultant for entrectinib and is a consultant/advisory board member for larotrectinib. L.V. Marshall has received speakers’ bureau honoraria from Bayer. A. von Deimling has received royalties for antibodies for clone H09 from Dianova (IDH1R132H) and for clone VE1 from Roche/Ventana (BRAFV600E). C.M. Kramm reports receiving a commercial research grant from Novartis and is a consultant/advisory board member for Novartis and Boehringer Ingelheim. F. Sahm has received speakers bureau honoraria from Illumina, Agilent, and Medac. D. Capper has ownership interest in a patent pending on DNA methylation–based tumor classification. No potential conflicts of interest were disclosed by the other authors. Funding Information: This work was supported by the CRIS Cancer Foundation and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Children’s Charity, and Children with Cancer UK, Cancer Research UK. The authors acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the ICR, the NIHR Great Ormond Street Hospital Biomedical Research Centre, research nurse funding by the Experimental Cancer Medicines Centre (ECMC) Paediatric Net-work, as well as CRUK support to the Cancer Imaging Centre at the ICR and Royal Marsden in association with the MRC and Department of Health (England; C1060/A16464). Further funding support was provided by the German Children’s Cancer Foundation (DKKS, project “MNP2.0 – Improving the Diagnostic Accuracy of Pediatric Brain Tumors,” and support for the German Brain Tumor Reference Center of the DGNN, grant 2014.17) and the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grant #01KU1201A), and the DKFZ-MOST Cooperation Program. We would like to thank Laura von Soosten (DKFZ) for technical assistance and Richard Buus (ICR) and the Breast Cancer Now NanoString facility for conducting the NanoString gene expression profiling. The authors thank Brain UK for provision of cases and clinical information. The authors thank the Cure Brain Cancer Foundation, Australian Lions Childhood Cancer Research Foundation, and Lions Club International Foundation (LCIF). Some of the results are in part based upon data generated by Lions Kids Cancer Genome Project (LKCGP) Partners. The authors thank the German Cancer Research Center (DKFZ) Genomics and Prot-eomics Core Facility and the Hartwell Center at St. Jude Children’s Research Hospital for technical support. The authors acknowledge funding from the American, Lebanese and Syrian-Associated Chari-ties (ALSAC). The Queensland Children’s Tumour Bank is funded by the Children’s Hospital Foundation (Queensland). This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748. We gratefully acknowledge the members of the Memorial Sloan Kettering Molecular Diagnostics Service in the Department of Pathology. M. Snuderl acknowledges funding from the Friedberg Charitable Foundation, the Making Headway Foundation, and the Sohn Conference Foun-dation. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Vinci is a CwCUK Fellow (grant number 16-234). S.J. Baker acknowledges funding support from the NIH (CA096832). Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/7

Y1 - 2020/7

N2 - Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrin-sic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.

AB - Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrin-sic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.

UR - http://www.scopus.com/inward/record.url?scp=85086156431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85086156431&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-19-1030

DO - 10.1158/2159-8290.CD-19-1030

M3 - Article

C2 - 32238360

AN - SCOPUS:85086156431

SN - 2159-8274

VL - 10

SP - 942

EP - 963

JO - Cancer Discovery

JF - Cancer Discovery

IS - 7

ER -

Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

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