Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Ana S Guerreiro Stucklin; Scott Ryall; Kohei Fukuoka; Michal Zapotocky; Alvaro Lassaletta; Christopher Li; Taylor Bridge; Byungjin Kim; Anthony Arnoldo; Paul E Kowalski; Yvonne Zhong; Monique Johnson; Claire Li; Arun K Ramani; Robert Siddaway; Liana Figueiredo Nobre; Pasqualino de Antonellis; Christopher Dunham; Sylvia Cheng; Daniel R Boué; Jonathan L Finlay; Scott L Coven; Inmaculada de Prada; Marta Perez-Somarriba; Claudia C Faria; Michael A Grotzer; Elisabeth Rushing; David Sumerauer; Josef Zamecnik; Lenka Krskova; Miguel Garcia Ariza; Ofelia Cruz; Andres Morales La Madrid; Palma Solano; Keita Terashima; Yoshiko Nakano; Koichi Ichimura; Motoo Nagane; Hiroaki Sakamoto; Maria Joao Gil-da-Costa; Roberto Silva; Donna L Johnston; Jean Michaud; Bev Wilson; Frank K H van Landeghem; Angelica Oviedo; P Daniel McNeely; Bruce Crooks; Iris Fried; Nataliya Zhukova; Jordan R Hansford; Amulya Nageswararao; Livia Garzia; Mary Shago; Michael Brudno; Meredith S Irwin; Ute Bartels; Vijay Ramaswamy; Eric Bouffet; Michael D Taylor; Uri Tabori; Cynthia Hawkins

doi:10.1038/s41467-019-12187-5

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Nat Commun. 2019 Sep 25;10(1):4343. doi: 10.1038/s41467-019-12187-5.

Authors

Ana S Guerreiro Stucklin^{1

2

3

4}, Scott Ryall^{1

2

5}, Kohei Fukuoka^{2

3}, Michal Zapotocky^{2

3

6}, Alvaro Lassaletta^{3

7}, Christopher Li^{1

2

5}, Taylor Bridge^{1

2}, Byungjin Kim^{1

2

5}, Anthony Arnoldo⁸, Paul E Kowalski⁸, Yvonne Zhong⁸, Monique Johnson⁸, Claire Li⁸, Arun K Ramani⁹, Robert Siddaway^{1

2}, Liana Figueiredo Nobre^{2

3}, Pasqualino de Antonellis^{1

2}, Christopher Dunham^{10

11}, Sylvia Cheng^{12

13}, Daniel R Boué^{14

15}, Jonathan L Finlay¹⁶, Scott L Coven¹⁶, Inmaculada de Prada¹⁷, Marta Perez-Somarriba⁷, Claudia C Faria^{18

19}, Michael A Grotzer⁴, Elisabeth Rushing²⁰, David Sumerauer⁶, Josef Zamecnik⁶, Lenka Krskova⁶, Miguel Garcia Ariza²¹, Ofelia Cruz²², Andres Morales La Madrid²², Palma Solano²³, Keita Terashima²⁴, Yoshiko Nakano²⁵, Koichi Ichimura²⁵, Motoo Nagane²⁶, Hiroaki Sakamoto²⁷, Maria Joao Gil-da-Costa²⁸, Roberto Silva²⁹, Donna L Johnston³⁰, Jean Michaud³¹, Bev Wilson³², Frank K H van Landeghem³³, Angelica Oviedo^{34

35}, P Daniel McNeely³⁶, Bruce Crooks³⁷, Iris Fried³⁸, Nataliya Zhukova³⁹, Jordan R Hansford^{39

40}, Amulya Nageswararao⁴¹, Livia Garzia⁴², Mary Shago^{5

8}, Michael Brudno⁹, Meredith S Irwin³, Ute Bartels³, Vijay Ramaswamy^{2

3}, Eric Bouffet³, Michael D Taylor^{1

2

5

43}, Uri Tabori^{1

2

3

44}, Cynthia Hawkins^{45

46

47

48}

Affiliations

¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
² The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
³ Department of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
⁵ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁶ Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
⁷ Department of Pediatric Hematology and Oncology, Hospital Universitario Niño Jesús, Madrid, Spain.
⁸ Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Division of Anatomic Pathology, British Columbia Children's Hospital, Vancouver, BC, Canada.
¹¹ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.
¹² Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada.
¹³ Division of Hematology/Oncology/BMT, British Columbia Children's Hospital, Vancouver, BC, Canada.
¹⁴ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁵ Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁶ Division of Hematology/Oncology/Bone Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁷ Department of Pathology, Hospital Universitario Niño Jesús, Madrid, Spain.
¹⁸ Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal.
¹⁹ Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
²⁰ Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
²¹ Department of Pediatric Oncology, Hospital Cruces, Bilbao, Spain.
²² Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
²³ Department of Pediatric Oncology, Hospital Infantil Virgen del Rocio, Sevilla, Spain.
²⁴ Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
²⁵ Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
²⁶ Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
²⁷ Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan.
²⁸ Division of Pediatric Hematoncology, University Hospital de São João, Porto, Portugal.
²⁹ Department of Pathology, University Hospital de São João, Porto, Portugal.
³⁰ Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
³¹ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
³² Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
³³ Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada.
³⁴ Department of Anatomic Pathology, Dalhousie University, Halifax, NS, Canada.
³⁵ Department of Pathology Laboratory Medicine, IWK Health Centre, Halifax, NS, Canada.
³⁶ Division of Neurosurgery, IWK Health Centre, Halifax, NS, Canada.
³⁷ Division of Hematology-Oncology, IWK Health Centre, Halifax, NS, Canada.
³⁸ The Department of Pediatric Hematology Oncology, Hadassah Medical Center, Jerusalem, Israel.
³⁹ Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia.
⁴⁰ Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Australia.
⁴¹ Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.
⁴² Department of Medicine, McGill University, Montreal, QC, Canada.
⁴³ Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
⁴⁴ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
⁴⁶ The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
⁴⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [email protected].
⁴⁸ Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].

Abstract

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase / genetics
Anaplastic Lymphoma Kinase / metabolism
Brain Neoplasms / classification
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
DNA Methylation*
Epigenomics / methods*
Exome Sequencing / methods
Female
Gene Expression Regulation, Neoplastic*
Glioma / classification
Glioma / genetics*
Glioma / metabolism
Humans
Infant
Infant, Newborn
Male
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism
Receptor Protein-Tyrosine Kinases / genetics*
Receptor Protein-Tyrosine Kinases / metabolism
Receptor, trkA / genetics
Receptor, trkA / metabolism
Survival Analysis

Substances

Proto-Oncogene Proteins
Anaplastic Lymphoma Kinase
MET protein, human
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-met
ROS1 protein, human
Receptor Protein-Tyrosine Kinases
Receptor, trkA

Abstract

Publication types

MeSH terms

Substances

Grants and funding