Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma
- Winnie S. Liang1,
- William Hendricks1,
- Jeffrey Kiefer1,
- Jessica Schmidt2,
- Shobana Sekar1,
- John Carpten1,
- David W. Craig1,
- Jonathan Adkins1,
- Lori Cuyugan1,
- Zarko Manojlovic1,
- Rebecca F. Halperin1,
- Adrienne Helland1,
- Sara Nasser1,
- Christophe Legendre1,
- Laurence H. Hurley3,
- Karthigayini Sivaprakasam1,
- Douglas B. Johnson4,
- Holly Crandall4,
- Klaus J. Busam5,
- Victoria Zismann1,
- Valerie Deluca1,
- Jeeyun Lee6,
- Aleksandar Sekulic1,2,
- Charlotte E. Ariyan5,8,
- Jeffrey Sosman7,8 and
- Jeffrey Trent1,8
- 1Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
- 2Mayo Clinic, Scottsdale, Arizona 85259, USA;
- 3University of Arizona, College of Pharmacy, Tucson, Arizona 85721, USA;
- 4Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA;
- 5Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
- 6Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
- 7Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, USA
- Corresponding author: jtrent{at}tgen.org
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↵8 These authors contributed equally to this work.
Abstract
Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (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.
Footnotes
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[Supplemental material is available for this article.]
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Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.213348.116.
- Received July 25, 2016.
- Accepted January 24, 2017.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
