title: Identification of a CpG island methylator phenotype in adrenocortical carcinomas.
abstract: OBJECTIVE
  DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression.
  
  
  METHODS
  Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors.
  
  
  RESULTS
  Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2).
  
  
  CONCLUSIONS
  This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Hortense
authors.initials: H
authors.lastname: Wilmot-Roussel
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Camille
authors.initials: C
authors.lastname: Baudry
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.forename: Nadim
authors.initials: N
authors.lastname: Hamzaoui
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reynies
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D018246:Adrenocortical Adenoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D018268:Adrenocortical Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D055815:Young Adult