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Genes Chromosomes Cancer. 2015 Sep;54(9):542-54. doi: 10.1002/gcc.22267. Epub 2015 May 29.

Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene.

Author information

1
Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT, 06520.
2
Department of Surgery, Yale School of Medicine, New Haven, CT.
3
Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, CCK, Stockholm, Sweden.
4
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT.
5
Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT.
6
Department of Genetics, Yale School of Medicine, New Haven, CT.
7
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT.
8
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-58185, Sweden.
9
Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
10
Department of Surgery, County Council of Östergötland, Linköping, SE-58185, Sweden.
11
Department of Pathology, Yale School of Medicine, New Haven, CT.
12
Yale Center for Mendelian Genomics, New Haven, CT.

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.

PMID:
26032282
PMCID:
PMC4755142
DOI:
10.1002/gcc.22267
[Indexed for MEDLINE]
Free PMC Article

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