title: SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes.
abstract: BACKGROUND
  Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization.
  
  
  OBJECTIVE
  We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients.
  
  
  RESULTS
  We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being -4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and -4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development.
  
  
  CONCLUSIONS
  Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.
authors.affiliation: Program Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 14 rue Corvisart, 75013 Paris, France. LetouzeE@ligue-cancer.net
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.forename: Roberto
authors.initials: R
authors.lastname: Rosati
authors.forename: Heloisa
authors.initials: H
authors.lastname: Komechen
authors.forename: Mabrouka
authors.initials: M
authors.lastname: Doghman
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marisa
authors.forename: Christa
authors.initials: C
authors.lastname: Flück
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Mas
authors.forename: Mara A D
authors.initials: MA
authors.lastname: Pianovski
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Bonald C
authors.initials: BC
authors.lastname: Figueiredo
authors.forename: Enzo
authors.initials: E
authors.lastname: Lalli
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D018246:Adrenocortical Adenoma / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D017668:Age of Onset; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D046228:Microarray Analysis; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics