title: ATRX driver mutation in a composite malignant pheochromocytoma.
abstract: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are tumors arising from the adrenal medulla and sympathetic/parasympathetic paraganglia, respectively. Approximately 40% of PCCs/PGLs are due to germline mutations in one of 16 susceptibility genes, and a further 30% are due to somatic alterations in 5 main genes. Recently, somatic ATRX mutations have been found in succinate dehydrogenase (SDH)-associated hereditary PCCs/PGLs. In the present study we applied whole-exome sequencing to the germline and tumor DNA of a patient with metastatic composite PCC and no alterations in known PCC/PGL susceptibility genes. A somatic loss-of-function mutation affecting ATRX was identified in tumor DNA. Transcriptional profiling analysis classified the tumor within cluster 2 of PCCs/PGLs (without SDH gene mutations) and identified downregulation of genes involved in neuronal development and homeostasis (NLGN4, CD99 and CSF2RA) as well as upregulation of Drosha, an important gene involved in miRNA and rRNA processing. CpG island methylator phenotype typical of SDH gene-mutated tumors was ruled out, and SNP array data revealed a unique profile of gains and losses. Finally, we demonstrated the presence of alternative lengthening of telomeres in the tumor, probably associated with the failure of ATRX functions. In conclusion, somatic variants affecting ATRX may play a driver role in sporadic PCC/PGL.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comino-Méndez
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Águeda M
authors.initials: ÁM
authors.lastname: Tejera
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Currás-Freixes
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Remacha
authors.affiliation: Department of Anatomical Pathology, Cabueñes Hospital, Gijón, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gonzalvo
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Tonda
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. Electronic address: acascon@cnio.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D000368:Aged; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D059472:Exome; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010673:Pheochromocytoma / Q000000981:diagnostic imaging / Q000235:genetics*; D020539:Sequence Analysis, Protein; D059505:Telomere Homeostasis / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ALT; ATRX; exome sequencing; pheochromocytoma