title: Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups.
abstract: OBJECTIVE
  To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.
  
  
  METHODS
  One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.
  
  
  RESULTS
  Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%-46.5% vs. 66.7%, 28.2%-87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%-71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.
  
  
  CONCLUSIONS
  Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs.
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Merino
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Shlien
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Villani
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pienkowska
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tatevossian
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Novokmet
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.affiliation: Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Dvir
authors.affiliation: Rambam Health Care Campus, Haifa, Israel.
authors.forename: Myran
authors.initials: M
authors.lastname: Ben-Arush
authors.affiliation: Georgetown University Medical Center, Washington, DC.
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
authors.affiliation: Children's National Medical Center, Washington, DC.
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Hwang
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Rishi
authors.initials: R
authors.lastname: Lulla
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Achatz
authors.affiliation: Montreal Children's Hospital, Montreal, Québec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Children's Hospital of Los Angeles, Los Angeles, California.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Finlay
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada. david.malkin@sickkids.ca.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016545:Choroid Plexus Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009367:Neoplasm Staging; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53