Highly recurrent TERT promoter mutations in human melanoma.
Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Franklin W
FW
Huang
Eran
E
Hodis
Mary Jue
MJ
Xu
Gregory V
GV
Kryukov
Lynda
L
Chin
Levi A
LA
Garraway
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D019098:Telomerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D050783:Proto-Oncogene Proteins c-ets; C509186:TERT protein, human; D019098:Telomerase