Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients

Currás-Freixes, María; Inglada-Pérez, Lucía; Mančíková, Veronika; Montero‐Conde, Cristina; Letón, Rocío; Comino-Méndez, Iñaki; Apellániz-Ruiz, María; Sánchez‐Barroso, Lara; Sánchez-Covisa, Miguel Aguirre; Alcázar, Victoria; Aller, Javier; Álvarez-Escolá, Cristina; Andía-Melero, Víctor M; Azriel-Mira, Sharona; Calatayud-Gutiérrez, María; Díaz, José Ángel; Díez-Hernández, Alberto; Oliveira, Cristina Lamas; Marazuela, Mónica; Matías‐Guiu, Xavier; Meoro-Avilés, Amparo; Patiño-García, Ana; Pedrinaci, Susana; Riesco‐Eizaguirre, Garcilaso; Sábado-Álvarez, Constantino; Sáez-Villaverde, Raquel; Terreros, Amaya Sainz de los; Guadarrama, Óscar Sanz; Sastre-Marcos, Júlia; Scolá-Yurrita, Bartolomé; Segura-Huerta, Ángel; Serrano-Corredor, Maria de la Soledad; Villar-Vicente, María Rosa; Rodríguez‐Antona, Cristina; Korpershoek, Esther; Cascón, Alberto; Robledo, Mercedes

doi:10.1136/jmedgenet-2015-103218

Cited by 109 publications

(85 citation statements)

References 54 publications

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“…methods that are well-established for detection of these genetic lesions, such as MLPA, quantitative multiplex PCR or other genome-wide copy number analysis assays, can be performed 43,44 . Alternatively, targeted NGS panels can be designed to optimize detection of larger deletions, insertions or rearrangements, as reported in hereditary breast cancer diagnostic panels 45 .…”

Section: Box 1 | Features Unique To Ppglsmentioning

confidence: 99%

“…In addition, special caution should be taken when designing primers that target areas of homology to pseudogenes or other partially homologous sequences, which can confound variant interpretation. Furthermore, the inclusion of just the hotspot exons of two PPGLs oncogenes, EPAS1 (exons 9 and 12) and RET (exons 8, 10, 11 and 13-16), instead of the entire coding region, was favoured for gene panels given the highly selective mutation distribution of these oncogenes 2,15,43,52 . However, these settings might need to be re-evaluated as the field evolves 53 .…”

Section: The Target Areamentioning

confidence: 99%

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Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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Section: Box 1 | Features Unique To Ppglsmentioning

confidence: 99%

Section: The Target Areamentioning

confidence: 99%

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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“…They belong to the family of pheochromocytoma/paraganglioma (PPGL). Although about 14% of apparently sporadic PHEOs are caused by germline mutations [1] . Patients with bilateral PHEOs and/or family history, carry germline mutations in most cases.…”

Section: Introductionmentioning

confidence: 99%

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

et al. 2016

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Background: In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC Associated Factor X) gene has been reported in a few cases. Here we investigated a 25 years old patient with multiple PHEOs associated with a non-sense germline MAX mutation. Preoperative 18F-FDOPA PET/CT revealed bilateral adrenal involvement with multiple tumors. In addition both adrenal glands were found to have diffuse or nodular adrenal medullary hyperplasia (AMH), a histopathological feature previously described as a precursor of MEN2 and SDHB-related PHEOs but not MAX. Materials and Methods: After bilateral adrenalectomy, different paraffin-embedded and frozen samples were analyzed for allelic imbalances of the MAX gene using allelic quantification by pyrosequencing. The expression of the protein MAX was studied by immunohistochemistry. Results: All PHEOs but also nodular AMH exhibited a loss of the normal allele. By contrast, the diffuse AMH did not show Loss-of-Heterozygosity. Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH. Conclusion: The present case shows that both nodular and diffuse AMH belongs to the spectrum of MAX-related disease. These data support the possible continuum between nodular AMH and PHEO, expanding the qualification of micro-PHEO to nodular AMH.

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“…The mutations result in two broad groups of tumors characterized by either activation of hypoxia or kinase receptor signaling pathways (1). Furthermore, somatic mutations in several of these genes or in two other PCC/PGL predisposition genes, HIF2A and HRAS (14,15), are found in an additional approximately 30% of tumors (16). Finally, 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.…”

Section: Introductionmentioning

confidence: 99%

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

Remacha

Comino-Méndez

Richter

et al. 2017

Clinical Cancer Research

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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 a-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. Ó2017 AACR.

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Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients

Cited by 109 publications

References 54 publications

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

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