title: A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.
abstract: OBJECTIVE
  Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma.
  
  
  METHODS
  Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.
  
  
  RESULTS
  Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded.
  
  
  CONCLUSIONS
  This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, Massachusetts.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shou
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, Massachusetts.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Robinson
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Dereck D
authors.initials: DD
authors.lastname: Amakye
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Rose
authors.affiliation: Departments of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, California.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Pediatric Neuro-Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Pathology, Children's Hospital Boston, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, Massachusetts.
authors.forename: Thad
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Asifa S
authors.initials: AS
authors.lastname: Haider
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, Massachusetts.
authors.forename: Raj
authors.initials: R
authors.lastname: Bandaru
authors.affiliation: Nagoya University Hospital, Nagoya, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Institut Gustave Roussy, University Paris-Sud, Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.affiliation: Institut Curie and University Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.affiliation: Deakin University/Barwon Health, Melbourne, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
authors.affiliation: Great Ormond Street Hospital for Children, London.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Hargrave
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Casanova
authors.affiliation: University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Tawbi
authors.affiliation: Vall d'Hebron Institut d'Oncologia, and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.affiliation: University of Leicester, Leicester, United Kingdom.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Thomas
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.affiliation: Children's Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
authors.affiliation: Pediatric Neuro-Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. mark_kieran@dfci.harvard.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D018579:Patient Selection; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib