title: Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas.
abstract: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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. Clin Cancer Res; 22(9); 2301-10. ©2015 AACR.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Toledo
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Zi-Ming
authors.initials: ZM
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Division of Orthopedic Surgery, Chiba Cancer Center, Chiba, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York.
authors.forename: Gustavo M
authors.initials: GM
authors.lastname: Silva
authors.affiliation: Department of Pathology, Yale University, New Haven, Connecticut.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: I Tolgay
authors.initials: IT
authors.lastname: Ocal
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Sarika
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.affiliation: Center for Endocrinological Investigations (CEDIE), Buenos Aires, Argentina.
authors.forename: Marta
authors.initials: M
authors.lastname: Barontini
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Jan
authors.initials: J
authors.lastname: Bruder
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.affiliation: Department of Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas.
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Cancer Therapy and Research Center (CTRC), University of Texas Health Science Center at San Antonio, San Antonio, Texas. Dahia@uthscsa.edu.
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000328:Adult; D000368:Aged; D018278:Carcinoma, Neuroendocrine / Q000235:genetics; D002648:Child; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D018212:Giant Cell Tumor of Bone / Q000235:genetics; D056466:Histone Demethylases / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics; D055815:Young Adult; D000076202:c-Mer Tyrosine Kinase / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D056466:Histone Demethylases; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000076202:c-Mer Tyrosine Kinase