The online version of this article (https://doi.org/10.1007/s00268-017-4320-0) contains supplementary material, which is available to authorized users.
Peter Söderkvist and Oliver Gimm have contributed equally to this manuscript.
Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with NF1 being the most common mutated gene (20–25%). In many sporadic tumors, however, a genetic explanation is still lacking.
We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas.
We discovered on average 33 non-silent somatic variants per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pediatric brain tumors. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1-, RET,- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways.
Besides RET and HRAS, FGFR1 is only the third protooncogene found to be recurrently mutated in pheochromocytomas. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of sporadic pheochromocytomas.
Supplementary material 1 (DOCX 655 kb)268_2017_4320_MOESM1_ESM.docx
The_Cancer_Genome_Atlas_Research_Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068 CrossRef
Lew ED, Furdui CM, Anderson KS et al (2009) The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci Signal 2:6 CrossRef
Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:l1 CrossRef
McInerney-Leo AM, Marshall MS, Gardiner B et al (2014) Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clin Endocrinol (Oxf) 80:25–33 CrossRef
- Activating FGFR1 Mutations in Sporadic Pheochromocytomas
- Springer International Publishing
Neu im Fachgebiet Chirurgie
Mail Icon II