Abstract
BackgroundSynonymous mutations have been identified to play important roles in cancer development, although they do not modify the protein sequences. However, relatively little research has specifically delineated the functionality of synonymous mutations in cancer.ResultsWe investigated the nucleotide-based and amino acid-based features of synonymous mutations across 15 cancer types from The Cancer Genome Atlas (TCGA), and revealed novel driver candidates by identifying hotspot mutations. Firstly, synonymous mutations were analyzed between TCGA and 1000 Genomes Project at nucleotide and amino acid levels. We found that C:G → T:A transitions were the most frequent single-base substitutions, and leucine underwent the largest number of synonymous mutations in TCGA due to prevalent C → T transition, which induced the transformation between optimal and non-optimal codons. Next, 97 synonymous hotspot mutations in 86 genes were nominated as candidate drivers with potential cancer risk by considering the mutational rates across different sequence contexts. We observed that non-CpG-island GC transition sequence context was positively selected across most of cancer types, and different sequence contexts under which hotspot mutations occur could be significance for genetic differences and functional features. We also found that the hotspots were more conserved than neutral mutations of hotspot-mutation-containing-genes and frequently happened at leucine. In addition, we mapped hotspots, neutral and non-hotspot mutations of hotspot-mutation-containing-genes to their respective protein domains and found ion transport domain was the most frequent one, which could mediate the cell interaction and had relevant implication for tumor therapy. And the signatures of synonymous hotspots were qualitatively similar with those of harmful missense variants.ConclusionsWe illustrated the preferences of cancer associated synonymous mutations, especially hotspots, and laid the groundwork for understanding the synonymous mutations act as drivers in cancer.
Highlights
Synonymous mutations have been identified to play important roles in cancer development, they do not modify the protein sequences
We got 373,434 cancer related synonymous mutations obtained from 5749 tumor samples across 15 types of cancer: breast cancer (BRCA), central nervous system tumor (CNST), cervical adenocarcinoma (CEAD), endometrial adenocarcinoma (ENAD), haematopoietic and lymphoid tumor (HLTU), kidney carcinoma (KICA), large intestine adenocarcinoma (INAD), liver carcinoma (LICA), lung adenocarcinoma (LUAD), ovarian carcinoma (OVCA), prostate adenocarcinoma (PRAD), skin cancer (SKCA), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA) and urinary tract carcinoma (UTCA)
Statistical analyses The majority of statistical analyses in this work were completed by using R, e.g., the distributions of synonymous variants across different cancer types, nucleotide substitutions and amino acids
Summary
Synonymous mutations have been identified to play important roles in cancer development, they do not modify the protein sequences. Synonymous mutations, which occur in the gene-coding regions without changing the encoded amino acids, have long been supposed to be silent for the fitness of organisms and neutral during evolution [1]. This conservative concept begins to be rebutted by two lines of evidence: first one is the understanding of synonymous mutational effect on protein synthesis and folding; second, codon usage bias reveals that synonymous codons are under evolutionary pressure [2]. Some studies have identified that synonymous mutations frequently act as driver mutations in human cancers [10, 11] and can affect clinical outcome or treatment response [12,13,14]
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