Project description:Familial pheochromocytoma (PCC) has been associated with germline mutations in 14 genes. Here we investigated three siblings, who presented with (metastatic) bilateral pheochromocytomas, renal oncocytoma, and erythrocytosis. By SNP-array on one patient’s germline DNA a large complex genomic alteration was identified encompassing the intragenic and promoter regions of Myc-Associated Factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). The alteration was confirmed in all patients, as well as loss of the wild type MAX and FUT8 alleles and corresponding loss of protein expression. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was also shown in the index patient by SNP-array. Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, MAX appears to be a new tumor suppressor gene for renal oncocytomas. SNP array was performed for 2 samples: 1 tumor DNA sample and 1 corresponding germline DNA sample
Project description:Familial pheochromocytoma (PCC) has been associated with germline mutations in 14 genes. Here we investigated three siblings, who presented with (metastatic) bilateral pheochromocytomas, renal oncocytoma, and erythrocytosis. By SNP-array on one patient’s germline DNA a large complex genomic alteration was identified encompassing the intragenic and promoter regions of Myc-Associated Factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). The alteration was confirmed in all patients, as well as loss of the wild type MAX and FUT8 alleles and corresponding loss of protein expression. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was also shown in the index patient by SNP-array. Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, MAX appears to be a new tumor suppressor gene for renal oncocytomas.
Project description:Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumours arising in the adrenal medulla and paraganglia of the autonomous nervous system, respectively. Malignant PCC/PGL are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Gene expression changes associated with SDHB inactivation were investigated in a two genetically defined murine cellular models. These models were generated by Cre-mediated recombination in spontaneously immortalized mouse chromaffin cells (imCCs) and adrenal fibroblasts (MAFs).
Project description:Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.
Project description:Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma. Oncocytoma and Chromophobe RCC samples - SNP chip analysis
Project description:Until now, it is nearly impossible to diagnose malignancy of pheochromocytoma/paraganglioma with pathological examinations. The aim of the study is to find the genes which can be applied as a biomarker in the clinic to distinguish benign and malignant forms of pheochromocytoma/paraganglioma.
Project description:Until now, it is nearly impossible to diagnose malignancy of pheochromocytoma/paraganglioma with pathological examinations. The aim of the study is to find the genes which can be applied as a biomarker in the clinic to distinguish benign and malignant forms of pheochromocytoma/paraganglioma. We generated aCGH profiles of 9 samples of benign tumors and 3 samples of malignant tumors
Project description:Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To establish whether PPGL phenotypic differences reflect a MAX-mediated mechanism and opposing influences of HIF2M-NM-1 and HIF1M-NM-1, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2M-NM-1, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1M-NM-1 has opposing actions to HIF2M-NM-1. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes. 88 samples (primary pheochromocytoma (PCC)/paraganglioma tumors) were hybridized onto a cDNA microarray in order to investigate possible heterogeneity within these tumors. This series of tumors is an expansion of GSE19422 that includes nine additional tumors to examine the role of MAX mutations in PCC/PGL.
