College of information science and engineering, Shaoguan University, Shaoguan, Guangdong, China.
Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China.
BMC Med Genomics. 2020 Apr 3;13(Suppl 5):43. doi: 10.1186/s12920-020-0685-2.
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.
非同义突变改变肿瘤抑制基因和癌基因的研究较为广泛。然而，同义突变（不改变蛋白质序列）在黑色素瘤基因组研究中很少被研究。
我们探索了 TCGA（癌症基因组图谱）中黑色素瘤样本中体细胞同义突变的作用。使用 Fisher 精确检验评估可能影响遗传调控元件的致病性同义突变在黑色素瘤中的重要性，同时使用致病同义突变和中性同义突变数据。使用泊松分布概率挖掘影响调控元件的具有多个潜在功能同义突变的基因。
集中在五种遗传调控功能上，我们发现致病性同义突变的突变模式主要涉及临近剪接位点的外显子剪接调节剂或内部 DNA 酶 I 超敏位点或非最优密码子。此外，miRNA 结合改变的位点的进化率明显低于其他位点。最后，12 个基因受到反复出现的潜在功能同义突变的影响，这些突变在致病性突变中具有统计学意义。其中，9 个基因（DNAH5、ADCY8、GRIN2A、KSR2、TECTA、RIMS2、XKR6、MYH1、SCN10A）已被报道在黑色素瘤中发生突变，另外三个基因（SLC9A2、CASR、SLC8A3）有很大的潜力影响黑色素瘤。
这些发现证实了体细胞同义突变在黑色素瘤中的功能后果，强调了在未来研究中进一步研究的意义。
