The original version of this chapter was previously published as non-open access.

Cancer arises when normal cells are transformed into malignant cells by acquiring a number of hallmarks such as sustained proliferative signaling; evading cell death, growth suppression and immune destruction; replicative immortality; and activation of invasion and metastasis (Hanahan et al. 2000, 2011). Sequential accumulation of genetic mutations is a major cause of acquiring these cancer hallmarks in the cell transformation process, and hence a complete characterization of the landscape of pathogenic somatic and congenital mutations in cancer cells forms a holy grail to fully understand cancer biology. Indeed, a lot of effort has gone towards characterizing somatic missense and nonsense single nucleotide variants in the protein coding regions of the genome that result in amino acid substitutions, small insertions and deletions, or a premature STOP codon in the encoded protein. Synonymous mutations on the other hand, nucleotide changes that do not result in an amino acid change in the protein for which they encode, have previously attracted significantly less at attention as candidate cancer driver mutations. However, in a variety of other diseases such as cystic fibrosis, ataxia telangiectasia and even in hereditary cancer syndromes, a causative role for synonymous mutations in disease pathogenesis has been described (Sauna et al. 2011). In addition, the number of synonymous mutations that have a significant impact on the corresponding RNA and protein expression level or isoform in different cancer types is rapidly rising. It is thus becoming clear that there might be a significant fraction of synonymous mutations that are not as ‘silent’ as they have long been considered to be. In this chapter, we will discuss why synonymous mutations have received little attention in the context of cancer. Furthermore, we will describe the recent progress that was made in characterizing the landscape of oncogenic synonymous mutations as well as the variety of molecular mechanisms by which synonymous mutations affect RNA and protein expression levels of oncogenes and tumor suppressors.