Abstract
Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1 A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio.Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315-24. ©2017 AACR.
Highlights
Despite their low prevalence, pheochromocytomas (PCC) and paragangliomas (PGL) represent a paradigm for hereditary cancer due to the highest degree of heritability of these tumors among all human neoplasms [1]
A truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered a-ketoglutarate/ isocitrate ratio
This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol
Summary
Pheochromocytomas (PCC) and paragangliomas (PGL) represent a paradigm for hereditary cancer due to the highest degree of heritability of these tumors among all human neoplasms [1]. The presence of features of heritability amongst some of the patients without germline mutations in the known susceptibility genes, strongly suggests the implication of additional genes in this multigenetic disease. More than half of the PCC/PGL predisposition genes encode enzymes involved in the Krebs cycle (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, and MDH2), which stresses the crucial role of this pathway in PCC/PGL development and suggests that alterations in other genes from this pathway could account for more patients.
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