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. |