Author Manuscript Published OnlineFirst on December 23, 2015; DOI: 10.1158/1078-0432.CCR-15-1841 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Recurrent mutations of chromatin remodeling genes and kinase receptors in pheochromocytomas and paragangliomas

Rodrigo A. Toledo1*, Yuejuan Qin1, Zi-Ming Cheng1, Qing Gao1, Shintaro Iwata2, Gustavo M. Silva3, Manju L. Prasad4, I. Tolgay Ocal5, Sarika Rao6, Neil Aronin6, Marta Barontini7, Jan Bruder1, Robert L. Reddick9, Yidong Chen10, Ricardo C. T. Aguiar1,11, Patricia L. M. Dahia1,11,¶.

Department of Medicine1, Department of Pathology9 and Department of Biostatistics10, Cancer Therapy and Research Center (CTRC)11, University of Texas Health Science Center at San Antonio, San Antonio, TX; Division of Orthopedic Surgery, Chiba Cancer Center, Chiba, Japan2; Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY3; Department of Pathology, Yale University, 200 South Frontage Rd, New Haven, CT4; Department of Lab Med and Pathology, Mayo Clinic Arizona, Scottsdale, AZ5; Department of Medicine, University of Massachusetts Medical School, Worcester, MA6; Center for Endocrinological Investigations (CEDIE), Buenos Aires, Argentina7

¶corresponding author: Patricia L. M. Dahia Dept. Medicine-University of Texas Health Science Center at San Antonio 7703 Floyd Curl Dr-MC7880 San Antonio-TX 78229 Tel: (210) 567 4866 Email: [email protected]

*current address: Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Conflict of Interest: The authors have no conflict of interest to declare.

Running title: Chromatin and kinase variants in paragangliomas

Keywords: pheochromocytomas, paragangliomas, giant cell tumor of the bone, histone, mutations, genetic, H3F3A, mosaic, chromatin, histone methyltransferases, histone demethylases, kinase, MET, MERTK, FGFR1, germline

Word count: 4,142

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Statement of translational relevance:

Pheochromocytomas and paragangliomas are genetically heterogeneous neuroendocrine tumors

caused by inherited mutations in 40% of the cases. Using exome or transcriptome sequencing we

identified novel recurrent germline, mosaic or somatic mutations in genes encoding chromatin

regulators, including histone and histone modifiers, as well as kinase receptors, among which were

MERTK, MET and FGFR1. Some of these mutations, in histone 3.3, MERTK and MET, were associated with co-occurring tumors or familial disease, suggesting that they belong to previously unappreciated susceptibility syndromes. These new variants increase the proportion of pheochromocytomas and paragangliomas with a known genetic basis and broaden the spectrum of genes targeted in these tumors. Furthermore, our findings provide new markers for genetic risk assessment. Future studies should define the utility of these data in the development of targeted therapeutic strategies for malignant or inoperable paragangliomas.

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Abstract

Purpose: Pheochromocytomas and paragangliomas (PPGLs) 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 amplico