Dataset Information

DNA methylation analysis in malignant pheochromocytoma and paraganglioma.

ABSTRACT: AIMS:In recent years, aberrant DNA methylation of specific CpG sites has been detected in many types of malignant tumors, and the epigenetic regulation of promoter CpG sites is considered an important mechanism underlying carcinogenesis. This study aimed to establish the epigenetics of the malignant transformation of malignant pheochromocytoma (PCC) and paraganglioma (PGL) by performing a methylation analysis. MATERIALS AND METHODS:Based on the results of the Infinium HumanMethylation450 BeadChip array using DNA samples of PCC/PGL patients, candidate CpG sites that were hyper/hypo-methylated in metastatic tumors relative to those in the primary tumors of 2 patients with malignant PCC/PGL were selected. The methylation levels of the chosen candidate CpG sites were evaluated quantitatively. RESULTS:Twelve CpG sites were selected as hypermethylated candidates, and 16 CpG sites were selected as hypomethylated candidates. Using two quantitative methylation analysis methods, one hypermethylated site (cg02119938) and one hypomethylated site (cg26870725) remained as candidates. These sites were related to ACSBG1 (acyl-CoA synthetase bubblegum family member 1) and MAST1 (microtubule-associated serine-threonine kinase 1), respectively. Immunohistochemical studies of ACSBG1 and MAST1 revealed that epigenetic changes in the malignant transformation of PCC/PGL might be associated with ACSBG1 silencing or MAST1 overexpression. CONCLUSIONS:Here, we report two noteworthy genes, ACSBG1 and MAST1; the aberrant promoter methylation/demethylation of these genes might be involved in their silencing/expression in malignant PCC/PGL. Further investigations are necessary to determine the role of ACSBG1 and/or MAST1 expression in malignant transformation and to establish pathological markers that can evaluate the malignant potential of PCC/PGL.

SUBMITTER: Oishi T

PROVIDER: S-EPMC5651299 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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DNA methylation analysis in malignant pheochromocytoma and paraganglioma.

Oishi Toshihiro T Iino Kazumi K Okawa Yuta Y Kakizawa Keisuke K Matsunari Shoko S Yamashita Miho M Taniguchi Terumi T Maekawa Masato M Suda Takafumi T Oki Yutaka Y

Journal of clinical & translational endocrinology 20161223

<h4>Aims</h4>In recent years, aberrant DNA methylation of specific CpG sites has been detected in many types of malignant tumors, and the epigenetic regulation of promoter CpG sites is considered an important mechanism underlying carcinogenesis. This study aimed to establish the epigenetics of the malignant transformation of malignant pheochromocytoma (PCC) and paraganglioma (PGL) by performing a methylation analysis.<h4>Materials and methods</h4>Based on the results of the Infinium HumanMethyla ...[more]

PMID: 29067245

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Project description:Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies. To identify druggable pathways driving PPGL development, we performed RNA sequencing on PPGLs (n = 19) and normal adrenal medullas (NAMs; n = 10) of dogs. Principal component analysis (PCA) revealed that PPGLs clearly clustered apart from NAMs. In total, 4,218 genes were differentially expressed between PPGLs and NAMs. Of these, 232 had a log2 fold change of >3 or < -3, of which 149 were upregulated in PPGLs, and 83 were downregulated. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle, tumor development, progression and metastasis, hypoxia and angiogenesis, and the Wnt signaling pathway, and decreased expression of genes related to adrenal steroidogenesis. Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as Ret Proto-Oncogene (RET), Dopamine Receptor D2 (DRD2), and Secreted Frizzled Related Protein 2 (SFRP2). Based on the PCA, PPGLs were classified into 2 groups, of which group 1 had significantly higher Ki67 scores (p = 0.035) and shorter survival times (p = 0.04) than group 2. Increased expression of 1 of the differentially expressed genes between group 1 and 2, pleiotrophin (PTN), appeared to correlate with a more aggressive tumor phenotype. This study has shed light on the transcriptomic profile of canine PPGL, yielding new insights into the pathogenesis of these tumors in dogs, and revealed potential novel targets for therapy. In addition, we identified 2 transcriptionally distinct groups of PPGLs that had significantly different survival times.

Project description:BackgroundGermline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.MethodsDNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293).ResultsUsing massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.ConclusionsOur studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.

Dataset Information

DNA methylation analysis in malignant pheochromocytoma and paraganglioma.

Publications

DNA methylation analysis in malignant pheochromocytoma and paraganglioma.

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