Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma

Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria ZismannValerie Deluca, Jeeyun Lee, Aleksandar D Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of nonultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15%of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

Original languageEnglish (US)
Pages (from-to)524-532
Number of pages9
JournalGenome Research
Volume27
Issue number4
DOIs
StatePublished - Apr 1 2017

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Liang, W. S., Hendricks, W., Kiefer, J., Schmidt, J., Sekar, S., Carpten, J., Craig, D. W., Adkins, J., Cuyugan, L., Manojlovic, Z., Halperin, R. F., Helland, A., Nasser, S., Legendre, C., Hurley, L. H., Sivaprakasam, K., Johnson, D. B., Crandall, H., Busam, K. J., ... Trent, J. (2017). Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma. Genome Research, 27(4), 524-532. https://doi.org/10.1101/gr.213348.116