title: Integrated genomic analyses reveal frequentTERTaberrations in acral melanoma.
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 driverBRAF/NRAS/NF1mutations. In contrast with CM, we observedPAK1copy gains in 15% of patients, and somaticTERTtranslocations, 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 ofTERTin ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hendricks
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kiefer
authors.affiliation: Mayo Clinic, Scottsdale, Arizona 85259, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Shobana
authors.initials: S
authors.lastname: Sekar
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: John
authors.initials: J
authors.lastname: Carpten
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adkins
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Cuyugan
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Manojlovic
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Halperin
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Helland
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Nasser
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: University of Arizona, College of Pharmacy, Tucson, Arizona 85721, USA.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Karthigayini
authors.initials: K
authors.lastname: Sivaprakasam
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Crandall
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismann
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Deluca
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.|Mayo Clinic, Scottsdale, Arizona 85259, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Sekulic
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Ariyan
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trent
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D054462:p21-Activated Kinases / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; C515903:PAK1 protein, human; D048493:Proto-Oncogene Proteins B-raf; D054462:p21-Activated Kinases; C509186:TERT protein, human; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human