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

Abstract

<div>Abstract<p><b>Purpose:</b> Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown.</p><p><b>Experimental Design:</b> 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. <i>In vitro</i> analysis of mutants was performed in cell lines.</p><p><b>Results:</b> 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, <i>H3F3A</i>. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of <i>MERT</i>K 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 <i>MET</i>, 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 <i>FGFR1</i> mutation was found in a sporadic tumor.</p><p><b>Conclusions:</b> This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. <i>MERTK</i>, <i>MET</i>, and <i>H3F3A</i> emerge as novel PPGL susceptibility genes. <i>Clin Cancer Res; 22(9); 2301–10. ©2015 AACR</i>.</p></div>