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

C. Christofer Juhlin, Adam Stenman, Felix Haglund, Victoria E. Clark, Taylor C. Brown, Jacob Baranoski, Kaya Bilguvar, Gerald Goh, Jenny Welander, Fredrika Svahn, Jill C. Rubinstein, Stefano Caramuta, Katsuhito Yasuno, Murat Günel, Martin Bäckdahl, Oliver Gimm, Peter Söderkvist, Manju L. Prasad, Reju Korah, Richard P. LiftonTobias Carling

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)542-554
Number of pages13
JournalGenes Chromosomes and Cancer
Volume54
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint Dive into the research topics of 'Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene'. Together they form a unique fingerprint.

  • Cite this

    Juhlin, C. C., Stenman, A., Haglund, F., Clark, V. E., Brown, T. C., Baranoski, J., Bilguvar, K., Goh, G., Welander, J., Svahn, F., Rubinstein, J. C., Caramuta, S., Yasuno, K., Günel, M., Bäckdahl, M., Gimm, O., Söderkvist, P., Prasad, M. L., Korah, R., ... Carling, T. (2015). Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes and Cancer, 54(9), 542-554. https://doi.org/10.1002/gcc.22267