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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. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT 2 D as a recurrently mutated gene