Synonymous Mutations Frequently Act as Driver Mutations in Human Cancers
A partir de données issues de divers travaux sur les génomes de cancer, cette étude montre que des mutations synonymes (qui modifient la séquence d'un gène sans directement altérer la séquence de la protéine codée) de certains oncogènes contribuent fréquemment au développement d'un cancer à travers divers mécanismes, notamment la régulation de l'épissage
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 32 UTRs. "Selection acts on synonymous mutations in oncogenes in human cancers "These mutations frequently alter exonic splicing motifs and affect mRNA splicing "TP53 also has recurrent synonymous mutations, but these inactivate splice sites "Dosage-sensitive oncogenes have recurrent mutations in their 32 UTRs Widespread selection on synonymous mutations has been demonstrated in human cancers. These silent mutations may act as cancer drivers through diverse molecular mechanisms such as regulating splicing.