Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors.
The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Annabelle L
AL
Fonseca
Johan
J
Kugelberg
Lee F
LF
Starker
Ute
U
Scholl
Murim
M
Choi
Per
P
Hellman
Göran
G
Åkerström
Gunnar
G
Westin
Richard P
RP
Lifton
Peyman
P
Björklund
Tobias
T
Carling
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic
D000077209:Decitabine; D001374:Azacitidine