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Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
Yale University, CT 06520 USA; Yale University, CT 06520 USA; Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Yale University, CT 06520 USA.
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2015 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 9, 542-554 p.Article in journal (Refereed) Published
Abstract [en]

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. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.

Place, publisher, year, edition, pages
Wiley: 12 months , 2015. Vol. 54, no 9, 542-554 p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-120721DOI: 10.1002/gcc.22267ISI: 000358384000002PubMedID: 26032282OAI: diva2:848277

Funding Agencies|Stockholm County Council; StratCan, Karolinska Institutet, Stockholm; Agency for Science, Technology and Research, Singapore; Cancer Society in Stockholm, Sweden; Damon Runyon Cancer Research Foundation; Ohse Research Award

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2015-08-25

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Welander, JennyGimm, OliverSöderkvist, Peter
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Division of Cell BiologyFaculty of Medicine and Health SciencesDivision of Clinical SciencesDepartment of Surgery in LinköpingDepartment of Clinical Pathology and Clinical Genetics
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