title: Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene.
abstract: As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development.
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.|Department of Surgery, Yale School of Medicine, New Haven, CT.|Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Stenman
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.affiliation: Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Clark
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.|Department of Surgery, Yale School of Medicine, New Haven, CT.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT.
authors.forename: Jacob
authors.initials: J
authors.lastname: Baranoski
authors.affiliation: Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-58185, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Welander
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
authors.forename: Fredrika
authors.initials: F
authors.lastname: Svahn
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.|Department of Surgery, Yale School of Medicine, New Haven, CT.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Rubinstein
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
authors.forename: Stefano
authors.initials: S
authors.lastname: Caramuta
authors.affiliation: Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT.|Department of Genetics, Yale School of Medicine, New Haven, CT.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-58185, Sweden.|Department of Surgery, County Council of Östergötland, Linköping, SE-58185, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-58185, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.|Department of Surgery, Yale School of Medicine, New Haven, CT.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT.|Yale Center for Mendelian Genomics, New Haven, CT.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.|Department of Surgery, Yale School of Medicine, New Haven, CT.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000209:etiology / Q000235:genetics*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010673:Pheochromocytoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020539:Sequence Analysis, Protein; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D020033:Protein Isoforms