Highly recurrent TERT promoter mutations in human melanoma

By Franklin W. Huang, Eran Hodis, M. Xu, G. Kryukov, Lynda Chin, Levi A. Garraway. Science, 2013

1,816 citations recorded by the source corpus.

Promoter Mutations and Cancer Cancer genome sequencing projects have highlighted the pathogenic role of recurrent mutations within the protein-coding regions of genes. Now, two studies suggest that the scope of mutations in human tumors extends to gene regulatory regions. In a study of 70 melanomas, Huang et al. (p. 957, published online 24 January) found that 71% harbored one of two specific mutations in the promoter region of TERT, the gene coding for the catalytic subunit of telomerase, the enzyme that caps chromosome ends. Independently, Horn et al. (p. 959, published online 24 January) identified a disease-segregating germline mutation in the TERT promoter in a family predisposed to melanoma and found additional TERT promoter mutations in a high percentage of sporadic melanomas and melanoma cell lines. The mutations in both studies generated new binding sites for specific transcription factors and, in reporter assays, caused an increase in transcription. A large fraction of human melanomas harbor mutations in sequences that regulate the expression of telomerase. 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.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/450fc10f1b234e1f86a73b7b8f4a6e8e8692df91

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Citations in the corpus

Frequency of TERT promoter mutations in human cancers (2013, result): “%) and by Huang et al.2 in a series of 70 melanomas and short-term cultures1,2.”
BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. (2014, background): “TERT C228T confers increased transcriptional activities of the TERT promoter by creating consensus binding motifs (GGA[A T] or CCGGAA) for E-twenty-six (ETS)/ternary complex transcription factors.(22,23) As activation of the mitogen-activated protein kinase pathway upregulates the ETS system,(24-26)”
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. (2015, background): “As such, non-exonic variants passing all previous criteria were redirected to a separate output file (intronic, untranslated region, intergenic, upstream) with the exception of TERT promoter variants that created new binding sites for ETS transcription factors.(23) Synonymous (ie, silent) exonic var”
Genomic Classification of Cutaneous Melanoma (2015, background): “TERT Promoter Mutations We confirmed mutually exclusive TERT promoter mutations C228T and C250T (Horn et al., 2013; Huang et al., 2013) in 23.”
High-Throughput Sequencing Technologies (2015, positive): “Moreover, WGS of cancer samples has also identified high-frequency, non-coding mutations, such as activating mutations in the TERT promoter (Huang et al., 2013), a poorly characterized but highly relevant class of somatic variants.”
Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics (2013, background): “Recently, three studies reported noncoding driver mutations in the TERT promoter in multiple tumor types, including melanomas and gliomas (10-12).”
Predicting the sequence specificities of DNA- and RNA-binding proteins by deep learning (2015, background): “Lastly, it was shown that mutations in the TERT (telomerase reverse transcriptase) promoter are linked to many types of aggressive cancer 41 , mostly by gain-of-function mutations creating ETS family 42,43 or GABP 41 transcription factor binding sites.”
Precision Oncology: The Road Ahead (2017, background): “Finally, going beyond coding region mutations, researchers are beginning to uncover recurrent and functional mutations in non-coding regions of the genome that might play a role in dysregulated gene expression, as is the case of the TERT promoter, shown to be mutated for the first time in melanoma [”
The somatic genomic landscape of chromophobe renal cell carcinoma (2014, background): “Although point mutations in the TERT promoter, leading to upregulation of TERT itself, have been recently reported in cancers such as melanoma (Heidenreich et al., 2014; Huang et al., 2013), our results represent another phenomenon, of recurrent genomic rearrangement breakpoints in the TERT promoter”