TERT Promoter Mutations in Familial and Sporadic Melanoma

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Science  24 Jan 2013:
DOI: 10.1126/science.1230062

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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 germ line 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/TCF transcription factors near the transcription start and in reporter gene assays, caused up to 2-fold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent UV signature somatic mutations in 125/168 (74%) of human cell lines derived from metastatic melanomas, corresponding metastatic tumor tissues (45/53, 85%) and in 25/77 (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.

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