Non-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. We 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. Concentrating 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. These findings confirm the functional consequences of somatic synonymous mutations in melanoma, emphasizing the significance of research in future studies.

中文翻译：

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调节元件中的体细胞同义突变有助于黑色素瘤的遗传病因

广泛研究了改变肿瘤抑制基因和癌基因的非同义突变。但是，在黑色素瘤基因组研究中很少研究不会改变蛋白质序列的同义突变。我们探讨了体细胞同义突变在TCGA（癌症基因组图谱）的黑色素瘤样品中的作用。使用Fisher精确检验，使用病原体同义突变和中性同义突变数据评估可能影响遗传调控元件的黑色素瘤中病原同义突变的重要性。每个基因的泊松分布概率被用于挖掘具有影响调节元件的多个潜在功能同义突变的基因。专注于五种类型的基因调控功能，我们发现，致病性同义突变的突变模式主要涉及在近剪接位点或DNase I超敏位点或非最佳密码子中的外显子剪接调节因子。而且，与其他位点相比，miRNA结合改变的位点表现出明显更低的进化速率。最后，12个基因被潜在的潜在功能性同义突变击中，这在致病突变中显示出统计学意义。其中，据报道有9个基因（DNAH5，ADCY8，GRIN2A，KSR2，TECTA，RIMS2，XKR6，MYH1，SCN10A）在黑素瘤中发生了突变，而其他三个基因（SLC9A2，CASR，SLC8A3）具有巨大的影响潜力黑色素瘤。这些发现证实了黑色素瘤中体细胞同义突变的功能后果，强调了未来研究的重要性。