Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas

Rodrigo A. Toledo, Yuejuan Qin, Zi Ming Cheng, Qing Gao, Shintaro Iwata, Gustavo M. Silva, Manju L. Prasad, I. Tolgay Ocal, Sarika Rao, Neil Aronin, Marta Barontini, Jan Bruder, Robert L. Reddick, Yidong Chen, Ricardo C.T. Aguiar, Patricia L.M. Dahia

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Purpose: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes.

Original languageEnglish (US)
Pages (from-to)2301-2310
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number9
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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