Lorena V Baroni1,2, Lakshmikirupa Sundaresan2, Ayala Heled2, Hallie Coltin1,2, Kristian W Pajtler3,4,5, Tong Lin6, Thomas E Merchant7, Roger McLendon8, Claudia Faria9, Molly Buntine10, Christine L White10, Stefan M Pfister3,4,5, Mark R Gilbert11, Terri S Armstrong11, Eric Bouffet1, Sachin Kumar2, Michael D Taylor2,12, Kenneth D Aldape13, David W Ellison14, Nicholas G Gottardo15, Marcel Kool3,4,16, Andrey Korshunov3,4,17, Jordan R Hansford18, Vijay Ramaswamy1,2,19. 1. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada. 2. Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. 3. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. 5. Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany. 6. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 7. Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 8. The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA. 9. Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal. 10. Hudson Institute of Medical Research, Clayton, Australia. 11. Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA. 12. Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada. 13. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. 14. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 15. Department of Paediatric Oncology and Haematology, Perth Children's Hospital, Perth, Australia. 16. Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. 17. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 18. Children's Cancer Centre, Royal Children's Hospital; Murdoch Children's Research Institute; Department of Pediatrics, University of Melbourne; Monash University, Melbourne, Australia. 19. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification. METHODS: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival. RESULTS: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group. CONCLUSIONS: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
BACKGROUND: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification. METHODS: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival. RESULTS: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group. CONCLUSIONS: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
Authors: Jill Bayliss; Piali Mukherjee; Chao Lu; Siddhant U Jain; Chan Chung; Daniel Martinez; Benjamin Sabari; Ashley S Margol; Pooja Panwalkar; Abhijit Parolia; Melike Pekmezci; Richard C McEachin; Marcin Cieslik; Benita Tamrazi; Benjamin A Garcia; Gaspare La Rocca; Mariarita Santi; Peter W Lewis; Cynthia Hawkins; Ari Melnick; C David Allis; Craig B Thompson; Arul M Chinnaiyan; Alexander R Judkins; Sriram Venneti Journal: Sci Transl Med Date: 2016-11-23 Impact factor: 17.956
Authors: Thomas E Merchant; Anne E Bendel; Noah D Sabin; Peter C Burger; Dennis W Shaw; Eric Chang; Shengjie Wu; Tianni Zhou; David D Eisenstat; Nicholas K Foreman; Christine E Fuller; Edwina Templeton Anderson; Juliette Hukin; Ching C Lau; Ian F Pollack; Fred H Laningham; Robert H Lustig; Floyd D Armstrong; Michael H Handler; Chris Williams-Hughes; Sandra Kessel; Mehmet Kocak; David W Ellison; Vijay Ramaswamy Journal: J Clin Oncol Date: 2019-02-27 Impact factor: 44.544
Authors: Kristian W Pajtler; Hendrik Witt; Martin Sill; David T W Jones; Volker Hovestadt; Fabian Kratochwil; Khalida Wani; Ruth Tatevossian; Chandanamali Punchihewa; Pascal Johann; Jüri Reimand; Hans-Jörg Warnatz; Marina Ryzhova; Steve Mack; Vijay Ramaswamy; David Capper; Leonille Schweizer; Laura Sieber; Andrea Wittmann; Zhiqin Huang; Peter van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Daniel Fults; Helen Toledano; Smadar Avigad; Lindsey M Hoffman; Andrew M Donson; Nicholas Foreman; Ekkehard Hewer; Karel Zitterbart; Mark Gilbert; Terri S Armstrong; Nalin Gupta; Jeffrey C Allen; Matthias A Karajannis; David Zagzag; Martin Hasselblatt; Andreas E Kulozik; Olaf Witt; V Peter Collins; Katja von Hoff; Stefan Rutkowski; Torsten Pietsch; Gary Bader; Marie-Laure Yaspo; Andreas von Deimling; Peter Lichter; Michael D Taylor; Richard Gilbertson; David W Ellison; Kenneth Aldape; Andrey Korshunov; Marcel Kool; Stefan M Pfister Journal: Cancer Cell Date: 2015-05-11 Impact factor: 31.743
Authors: Florence M G Cavalli; Marc Remke; Ladislav Rampasek; John Peacock; David J H Shih; Betty Luu; Livia Garzia; Jonathon Torchia; Carolina Nor; A Sorana Morrissy; Sameer Agnihotri; Yuan Yao Thompson; Claudia M Kuzan-Fischer; Hamza Farooq; Keren Isaev; Craig Daniels; Byung-Kyu Cho; Seung-Ki Kim; Kyu-Chang Wang; Ji Yeoun Lee; Wieslawa A Grajkowska; Marta Perek-Polnik; Alexandre Vasiljevic; Cecile Faure-Conter; Anne Jouvet; Caterina Giannini; Amulya A Nageswara Rao; Kay Ka Wai Li; Ho-Keung Ng; Charles G Eberhart; Ian F Pollack; Ronald L Hamilton; G Yancey Gillespie; James M Olson; Sarah Leary; William A Weiss; Boleslaw Lach; Lola B Chambless; Reid C Thompson; Michael K Cooper; Rajeev Vibhakar; Peter Hauser; Marie-Lise C van Veelen; Johan M Kros; Pim J French; Young Shin Ra; Toshihiro Kumabe; Enrique López-Aguilar; Karel Zitterbart; Jaroslav Sterba; Gaetano Finocchiaro; Maura Massimino; Erwin G Van Meir; Satoru Osuka; Tomoko Shofuda; Almos Klekner; Massimo Zollo; Jeffrey R Leonard; Joshua B Rubin; Nada Jabado; Steffen Albrecht; Jaume Mora; Timothy E Van Meter; Shin Jung; Andrew S Moore; Andrew R Hallahan; Jennifer A Chan; Daniela P C Tirapelli; Carlos G Carlotti; Maryam Fouladi; José Pimentel; Claudia C Faria; Ali G Saad; Luca Massimi; Linda M Liau; Helen Wheeler; Hideo Nakamura; Samer K Elbabaa; Mario Perezpeña-Diazconti; Fernando Chico Ponce de León; Shenandoah Robinson; Michal Zapotocky; Alvaro Lassaletta; Annie Huang; Cynthia E Hawkins; Uri Tabori; Eric Bouffet; Ute Bartels; Peter B Dirks; James T Rutka; Gary D Bader; Jüri Reimand; Anna Goldenberg; Vijay Ramaswamy; Michael D Taylor Journal: Cancer Cell Date: 2017-06-12 Impact factor: 31.743
Authors: Florence M G Cavalli; Jens-Martin Hübner; Tanvi Sharma; Betty Luu; Martin Sill; Michal Zapotocky; Stephen C Mack; Hendrik Witt; Tong Lin; David J H Shih; Ben Ho; Mariarita Santi; Lyndsey Emery; Juliette Hukin; Christopher Dunham; Roger E McLendon; Eric S Lipp; Sridharan Gururangan; Andrew Grossbach; Pim French; Johan M Kros; Marie-Lise C van Veelen; Amulya A Nageswara Rao; Caterina Giannini; Sarah Leary; Shin Jung; Claudia C Faria; Jaume Mora; Ulrich Schüller; Marta M Alonso; Jennifer A Chan; Almos Klekner; Lola B Chambless; Eugene I Hwang; Maura Massimino; Charles G Eberhart; Matthias A Karajannis; Benjamin Lu; Linda M Liau; Massimo Zollo; Veronica Ferrucci; Carlos Carlotti; Daniela P C Tirapelli; Uri Tabori; Eric Bouffet; Marina Ryzhova; David W Ellison; Thomas E Merchant; Mark R Gilbert; Terri S Armstrong; Andrey Korshunov; Stefan M Pfister; Michael D Taylor; Kenneth Aldape; Kristian W Pajtler; Marcel Kool; Vijay Ramaswamy Journal: Acta Neuropathol Date: 2018-07-17 Impact factor: 17.088
Authors: M Carter; J Nicholson; F Ross; J Crolla; R Allibone; V Balaji; R Perry; D Walker; R Gilbertson; D W Ellison Journal: Br J Cancer Date: 2002-03-18 Impact factor: 7.640
Authors: Volker Hovestadt; Marc Remke; Marcel Kool; Torsten Pietsch; Paul A Northcott; Roger Fischer; Florence M G Cavalli; Vijay Ramaswamy; Marc Zapatka; Guido Reifenberger; Stefan Rutkowski; Matthias Schick; Melanie Bewerunge-Hudler; Andrey Korshunov; Peter Lichter; Michael D Taylor; Stefan M Pfister; David T W Jones Journal: Acta Neuropathol Date: 2013-05-14 Impact factor: 17.088
Authors: Amr H Saleh; Nardin Samuel; Kyle Juraschka; Mohammad H Saleh; Michael D Taylor; Michael G Fehlings Journal: Nat Rev Cancer Date: 2022-01-14 Impact factor: 69.800
Authors: Michael Zhang; Edward Wang; Derek Yecies; Lydia T Tam; Michelle Han; Sebastian Toescu; Jason N Wright; Emre Altinmakas; Eric Chen; Alireza Radmanesh; Jordan Nemelka; Ozgur Oztekin; Matthias W Wagner; Robert M Lober; Birgit Ertl-Wagner; Chang Y Ho; Kshitij Mankad; Nicholas A Vitanza; Samuel H Cheshier; Tom S Jacques; Paul G Fisher; Kristian Aquilina; Mourad Said; Alok Jaju; Stefan Pfister; Michael D Taylor; Gerald A Grant; Sarah Mattonen; Vijay Ramaswamy; Kristen W Yeom Journal: Neuro Oncol Date: 2022-06-01 Impact factor: 13.029