TERT promoter mutations in familial and sporadic melanoma.
Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors.
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Susanne
S
Horn
Adina
A
Figl
P Sivaramakrishna
PS
Rachakonda
Christine
C
Fischer
Antje
A
Sucker
Andreas
A
Gast
Stephanie
S
Kadel
Iris
I
Moll
Eduardo
E
Nagore
Kari
K
Hemminki
Dirk
D
Schadendorf
Rajiv
R
Kumar
D001665:Binding Sites; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D050808:ets-Domain Protein Elk-4 / Q000378:metabolism
D050783:Proto-Oncogene Proteins c-ets; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; C509186:TERT protein, human; D019098:Telomerase