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Cell. 2014 Mar 13;156(6):1324-1335. doi: 10.1016/j.cell.2014.01.051.

Synonymous mutations frequently act as driver mutations in human cancers.

Author information

1
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Dr. Aiguader 88, 08003 Barcelona, Spain; Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona 08003, Spain.
2
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation, Dr. Aiguader 88, 08003 Barcelona, Spain; Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona 08003, Spain.
3
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation, Dr. Aiguader 88, 08003 Barcelona, Spain; Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona 08003, Spain; Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain.
4
Bioinformatics and Genomics Program, Centre for Genomic Regulation, Dr. Aiguader 88, 08003 Barcelona, Spain; Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona 08003, Spain; Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain.
5
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Dr. Aiguader 88, 08003 Barcelona, Spain; Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona 08003, Spain; Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain. Electronic address: ben.lehner@crg.eu.

Abstract

Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Here, we present evidence that these "silent" mutations frequently contribute to human cancer. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them. We estimate that between one in two and one in five silent mutations in oncogenes have been selected, equating to ~6%- 8% of all selected single-nucleotide changes in these genes. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3' UTRs.

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PMID:
24630730
DOI:
10.1016/j.cell.2014.01.051
[Indexed for MEDLINE]
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