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 Zismann; Valerie Deluca; Jeeyun Lee; Aleksandar Sekulic; Charlotte E. Ariyan; Jeffrey Sosman; Jeffrey Trent

doi:10.1101/gr.213348.116

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 Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent

Dermatology

Research output: Contribution to journal › Article › peer-review

51 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 language	English (US)
Pages (from-to)	524-532
Number of pages	9
Journal	Genome Research
Volume	27
Issue number	4
DOIs	https://doi.org/10.1101/gr.213348.116
State	Published - Apr 2017

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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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

Liang, WS, Hendricks, W, Kiefer, J, Schmidt, J, Sekar, S, Carpten, J, Craig, DW, Adkins, J, Cuyugan, L, Manojlovic, Z, Halperin, RF, Helland, A, Nasser, S, Legendre, C, Hurley, LH, Sivaprakasam, K, Johnson, DB, Crandall, H, Busam, KJ, Zismann, V, Deluca, V, Lee, J, Sekulic, A, Ariyan, CE, Sosman, J & Trent, J 2017, 'Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma', Genome Research, vol. 27, no. 4, pp. 524-532. https://doi.org/10.1101/gr.213348.116

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title = "Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma",

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.",

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

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year = "2017",

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doi = "10.1101/gr.213348.116",

language = "English (US)",

volume = "27",

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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

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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Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma

Abstract

ASJC Scopus subject areas

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