Integrative epigenomic and genomic analysis of malignant pheochromocytoma.
Epigenomic and genomic changes affect gene expression and contribute to tumor development. The histone modifications trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) are epigenetic regulators associated to active and silenced genes, respectively and alterations of these modifications have been observed in cancer. Furthermore, genomic aberrations such as DNA copy number changes are common events in tumors. Pheochromocytoma is a rare endocrine tumor of the adrenal gland that mostly occurs sporadic with unknown epigenetic/genetic cause. The majority of cases are benign. Here we aimed to combine the genome-wide profiling of H3K4me3 and H3K27me3, obtained by the ChIP-chip methodology, and DNA copy number data with global gene expression examination in a malignant pheochromocytoma sample. The integrated analysis of the tumor expression levels, in relation to normal adrenal medulla, indicated that either histone modifications or chromosomal alterations, or both, have great impact on the expression of a substantial fraction of the genes in the investigated sample. Candidate tumor suppressor genes identified with decreased expression, a H3K27me3 mark and/or in regions of deletion were for instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, PTPRE and CDH11. More genes were found with increased expression, a H3K4me3 mark, and/or in regions of gain. Potential oncogenes detected among those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, IGF2, and the H3K27 trimethylase gene EZH2. Our approach to associate histone methylations and DNA copy number changes to gene expression revealed apparent impact on global gene transcription, and enabled the identification of candidate tumor genes for further exploration.
Department of Surgical Sciences, Uppsala University, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
Johanna
J
Sandgren
Robin
R
Andersson
Alvaro
A
Rada-Iglesias
Stefan
S
Enroth
Goran
G
Akerstrom
Jan P
JP
Dumanski
Jan
J
Komorowski
Gunnar
G
Westin
Claes
C
Wadelius
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology*; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D006657:Histones; D025521:Tumor Suppressor Proteins; D008239:Lysine