Identification of a CpG island methylator phenotype in adrenocortical carcinomas
Olivia Barreau1, Guillaume Assié, Hortense Wilmot-Roussel
1Institut 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.
Purpose:
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.
Experimental Design:
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.
Insights
Hypermethylated adrenocortical carcinomas exhibit a poorer prognosis and are linked to silenced tumor suppressor genes. This genome-wide DNA methylation study reveals distinct methylation profiles in these aggressive tumors.
Area of Science:
- Endocrinology
- Cancer Biology
- Epigenetics
Background:
- DNA methylation is a key epigenetic regulator of gene expression, crucial in cancer development.
- Adrenocortical tumors, particularly carcinomas, show limited characterization regarding their methylation landscape.
- Aberrant methylation at the IGF2/H19 locus is a known feature of adrenocortical carcinomas.
Purpose of the Study:
- To perform a genome-wide methylation analysis of adrenocortical carcinomas.
- To investigate the clinical significance of DNA methylation patterns in these tumors.
- To assess the impact of methylation on gene expression in adrenocortical carcinomas.
Main Methods:
- Genome-wide DNA methylation profiling using Infinium HumanMethylation27 Beadchip on 51 adrenocortical carcinomas and 84 adenomas.
- Validation of methylation status for 33 genes using methylation-specific multiplex ligation-dependent probe amplification in 15 carcinomas.
- Correlation of methylation data with gene expression data from 87 tumors and clinical information.
Main Results:
- DNA methylation levels were significantly higher in adrenocortical carcinomas compared to adenomas (P = 3.1 × 10(-9)).
- Unsupervised clustering identified distinct subgroups of carcinomas based on methylation, including a CpG island methylator phenotype (CIMP-high and CIMP-low).
- Hypermethylation was significantly associated with poorer patient survival (P = 0.02) and correlated with the silencing of tumor suppressor genes like H19, PLAGL-1, G0S2, and NDRG2.
Conclusions:
- Genome-wide methylation analysis confirms the existence of hypermethylated adrenocortical carcinomas with a worse prognosis.
- Epigenetic alterations, specifically hypermethylation, play a critical role in silencing tumor suppressor genes in adrenocortical carcinomas.
- These findings highlight DNA methylation as a potential biomarker and therapeutic target in adrenocortical carcinoma.
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