Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma
Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma
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DOI：
10.1073/pnas.1304227110
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发表时间：
2013-08-13
影响因子：
11.1
通讯作者：
Samuels, Yardena
中科院分区：
文献类型：
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作者：
Gartner, Jared J.;Parker, Stephen C. J.;Samuels, Yardena
同义突变不会改变蛋白质序列，但已被证明会影响蛋白质功能[Sauna ZE, Kimchi - Sarfaty C (2011)《自然综述：遗传学》12(10):683 - 691]。然而，在癌症基因组学领域，同义突变很少被研究。我们利用全基因组和外显子组测序来鉴定29个黑色素瘤样本中的体细胞突变。对285个样本中BCL2L12的一个同义体细胞突变进行验证，发现12个病例存在反复出现的F17F突变。由于hsa - miR - 671 - 5p对野生型和突变型BCL2L12的靶向差异，该突变导致BCL2L12的mRNA和蛋白质水平升高。由突变型BCL2L12转录本产生的蛋白质与p53结合，比野生型BCL2L12更有效地抑制紫外线诱导的细胞凋亡，并降低内源性p53靶基因的转录。本报告显示了癌症中一种反复出现的体细胞同义突变的选择。我们的数据表明，沉默改变在人类癌症中起作用，强调了在未来癌症基因组研究中对其进行研究的重要性。
Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies.