TY - JOUR
T1 - Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma
AU - Liang, Winnie S.
AU - Hendricks, William
AU - Kiefer, Jeffrey
AU - Schmidt, Jessica
AU - Sekar, Shobana
AU - Carpten, John
AU - Craig, David W.
AU - Adkins, Jonathan
AU - Cuyugan, Lori
AU - Manojlovic, Zarko
AU - Halperin, Rebecca F.
AU - Helland, Adrienne
AU - Nasser, Sara
AU - Legendre, Christophe
AU - Hurley, Laurence H.
AU - Sivaprakasam, Karthigayini
AU - Johnson, Douglas B.
AU - Crandall, Holly
AU - Busam, Klaus J.
AU - Zismann, Victoria
AU - Deluca, Valerie
AU - Lee, Jeeyun
AU - Sekulic, Aleksandar
AU - Ariyan, Charlotte E.
AU - Sosman, Jeffrey
AU - Trent, Jeffrey
N1 - Funding Information:
This publication is based on research supported by the Melanoma Research Alliance (MRA) - Hidary Foundation Team Science Award for Acral Melanoma Genomics (J. Sosman, C.E. Ariyan, and J. Trent, PI's). Additionally, the research was supported in part by TGen, the TGen Foundation, and a Stand Up To Cancer (SU2C) - Melanoma Research Alliance Melanoma Dream Team Translational Cancer Research Grant (#SU2C-AACR-DT0612). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. The authors thank the patients and their families for participating in this study. We additionally thank TGen's Seungchan Kim for RNA-seq analysis feedback; Jessica Aldrich, Daniel Enriquez, and Fatima Naveed for assistance with bioinformatics; and Cassandra Lucas, Cynthia Lechuga, and Kati Koktavy (TGen) for administrative support.
Publisher Copyright:
©2017 Liang et al.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.213348.116
DO - 10.1101/gr.213348.116
M3 - Article
C2 - 28373299
AN - SCOPUS:85017538373
SN - 1088-9051
VL - 27
SP - 524
EP - 532
JO - Genome Research
JF - Genome Research
IS - 4
ER -