Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and paragangliomas.

July 25, 2017

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Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and paragangliomas.

Publicated to:Clinical Cancer Research. (): 6315-6325 - 2017-10-15 (), DOI: 10.1158/1078-0432.CCR-16-2250

Authors: Remacha L, Comino-Méndez I, Richter S, Contreras L, Currás-Freixes M, Pita G, Letón R, Galarreta A, Torres-Pérez R, Honrado E, Jiménez S, Maestre L, Moran S, Esteller M, Satrústegui J, Eisenhofer G, Robledo M, Cascón A

Affiliations

Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain - Author

Cascon, Alberto - Author

Comino-Mendez, Inaki - Author

Contreras, Laura - Author

Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain - Author

Curras-Freixes, Maria - Author

Eisenhofer, Graeme - Author

Esteller, Manel - Author

FJD, IIS, Madrid, Spain - Author

Galarreta, Antonio - Author

Honrado, Emiliano - Author

Hosp Leon, Anat Pathol Serv, Leon, Spain - Author

Jimenez, Scherezade - Author

Leton, Rocio - Author

Maestre, Lorena - Author

Moran, Sebastian - Author

Pita, Guillermo - Author

Remacha, Laura - Author

Richter, Susan - Author

Robledo, Mercedes - Author

Satrustegui, Jorgina - Author

Spanish Natl Canc Res Ctr CNIO, Biotechnol Program, Monoclonal Antibodies Unit, Madrid, Spain - Author

Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain - Author

Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping Unit CeGen, Madrid, Spain - Author

Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Med Fac Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany - Author

Torres-Perez, Rafael - Author

Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa UAM, Dept Biol Mol, CSIC, Madrid, Spain - Author

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 ?-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.©2017 American Association for Cancer Research.

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The work has been published in the journal Clinical Cancer Research due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 12/223, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.89. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

Weighted Average of Normalized Impact by the Scopus agency: 2.32 (source consulted: FECYT Feb 2024)
Field Citation Ratio (FCR) from Dimensions: 13.73 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-16, the following number of citations:

WoS: 57
Scopus: 73
Europe PMC: 35

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This work has been carried out with international collaboration, specifically with researchers from: Germany.

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Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and paragangliomas.

Affiliations

Abstract

Keywords

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

Impact and social visibility

Leadership analysis of institutional authors