Abstract
BackgroundNon-synonymous mutations altering tumor suppressor genes and oncogenes are widely studied. However, synonymous mutations, which do not alter the protein sequence, are rarely investigated in melanoma genome studies.MethodsWe explored the role of somatic synonymous mutations in melanoma samples from TCGA (The Cancer Genome Atlas). The pathogenic synonymous mutation and neutral synonymous mutation data were used to assess the significance of pathogenic synonymous mutations in melanoma likely to affect genetic regulatory elements using Fisher’s exact test. Poisson distribution probabilities of each gene were used to mine the genes with multiple potential functional synonymous mutations affecting regulatory elements.ResultsConcentrating on five types of genetic regulatory functions, we found that the mutational patterns of pathogenic synonymous mutations are mostly involved in exonic splicing regulators in near-splicing sites or inside DNase I hypersensitivity sites or non-optimal codon. Moreover, the sites of miRNA binding alteration exhibit a significantly lower rate of evolution than other sites. Finally, 12 genes were hit by recurrent potentially functional synonymous mutations, which showed statistical significance in the pathogenic mutations. Among them, nine genes (DNAH5, ADCY8, GRIN2A, KSR2, TECTA, RIMS2, XKR6, MYH1, SCN10A) have been reported to be mutated in melanoma, and other three genes (SLC9A2, CASR, SLC8A3) have a great potential to impact melanoma.ConclusionThese findings confirm the functional consequences of somatic synonymous mutations in melanoma, emphasizing the significance of research in future studies.
Highlights
Non-synonymous mutations altering tumor suppressor genes and oncogenes are widely studied
To test whether somatic synonymous mutations can induce the genetic aetiology of melanoma, we mainly focused on five mechanisms: splicing regulation, transcription factor binding, miRNA binding, codon optimality, and the RNA second structure to analyse their impact on melanoma (Fig. 1) [11]
Our findings present statistical evidence that pathogenic synonymous mutations in melanoma may act through changing exonic splicing regulators in near-splicing sites, altering DNase I hypersensitivity sites, and likely losing optimal codons
Summary
Non-synonymous mutations altering tumor suppressor genes and oncogenes are widely studied. Synonymous mutations, which do not alter the protein sequence, are rarely investigated in melanoma genome studies. Significant efforts have been made in cancer genomic sequencing by a large consortium. Previous studies have indicated that somatic synonymous mutations are associated with a risk of cancer. Increasing evidence suggests that these synonymous mutations can lead to major splicing defects at the mRNA level or codon usage or function regions annotation features and cause disease [3,4,5,6]. Systematic melanoma sequencing studies have identified multiple recurrent mutations that impose functional consequences on the progression of melanoma [7, 8].
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