Abstract
Codon optimality has been demonstrated to be an important determinant of mRNA stability and expression levels in multiple model organisms and human cell lines. However, tissue-specific codon optimality has not been developed to investigate how codon optimality is usually perturbed by somatic synonymous mutations in human cancers. Here, we determined tissue-specific codon optimality in 29 human tissues based on mRNA expression data from the Genotype-Tissue Expression project. We found that optimal codons were associated with differentiation, whereas non-optimal codons were correlated with proliferation. Furthermore, codons biased toward differentiation displayed greater tissue specificity in codon optimality, and the tissue specificity of codon optimality was primarily present in amino acids with high degeneracy of the genetic code. By applying tissue-specific codon optimality to somatic synonymous mutations in 8532 tumor samples across 24 cancer types and to those in 416 normal cells across six human tissues, we found that synonymous mutations frequently increased optimal codons in tumor cells and cancer-related genes (e.g., genes involved in cell cycle). Furthermore, an elevated frequency of optimal codon gain was found to promote tumor cell proliferation in three cancer types characterized by DNA damage repair deficiency and could act as a prognostic biomarker for patients with triple-negative breast cancer. In summary, this study profiled tissue-specific codon optimality in human tissues, revealed alterations in codon optimality caused by synonymous mutations in human cancers, and highlighted the non-negligible role of optimal codon gain in tumorigenesis and therapeutics.