Incorporating mutational heterogeneity to identify genes that are enriched for synonymous mutations in cancer.
Incorporating mutational heterogeneity to identify genes that are enriched for synonymous mutations in cancer.
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DOI：
10.1186/s12859-023-05521-8
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发表时间：
2023-12-07
影响因子：
3
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中科院分区：
文献类型：
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同义突变改变DNA序列但不改变编码的蛋白质序列，可影响蛋白质结构和功能、mRNA成熟和mRNA半衰期。最近的几项研究探讨了同义突变可能在癌症中富集的可能性。然而，这些研究都没有控制所有三种类型的突变异质性（患者，组织学和基因），这些突变异质性已知会影响非同义癌症相关基因的准确识别。我们的目标是在同义突变的研究中采用目前的非同义突变标准。在这里，我们创建了一个算法，MutSigCVsyn，MutSigCV的适应，以确定癌症相关的基因，这些基因基于非编码背景模型，考虑到这些水平的突变异质性，富含同义突变。使用MutSigCVsyn，我们首先分析了来自全基因组泛癌症分析（PCAWG）的2572个癌症全基因组样本，以识别非同义癌症驱动因素作为质量控制。我们发现这些候选基因中有58.6%也在癌症普查基因（CGC）列表中找到，66.2%在PCAWG癌症驱动列表中找到。然后，我们将其应用于确定30个推定的癌症相关基因，这些基因在相同的样本中富含同义突变。B细胞淋巴瘤2（BCL-2）基因是有希望的候选基因之一。BCL-2通过拮抗促凋亡BCL-2家族成员蛋白的作用来调节凋亡。BCL 2中的同义突变在其抗凋亡结构域中富集，并且可能在癌细胞增殖中起作用。我们的研究引入了MutSigCVsyn，这是一种在患者，组织学和基因水平上解释突变异质性的算法，用于使用全基因组测序数据识别富含同义突变的癌症相关基因。我们确定了30个假定的候选基因，这些基因将受益于未来关于同义突变在癌症生物学中作用的实验研究。在线版本包含补充材料，可通过10.1186/s12859-023-05521-8获得。
Synonymous mutations, which change the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations might be enriched in cancer has been explored in several recent studies. However, none of these studies control for all three types of mutational heterogeneity (patient, histology, and gene) that are known to affect the accurate identification of non-synonymous cancer-associated genes. Our goal is to adopt the current standard for non-synonymous mutations in an investigation of synonymous mutations. Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify cancer-associated genes that are enriched for synonymous mutations based on a non-coding background model that takes into account the mutational heterogeneity across these levels. Using MutSigCVsyn, we first analyzed 2572 cancer whole-genome samples from the Pan-cancer Analysis of Whole Genomes (PCAWG) to identify non-synonymous cancer drivers as a quality control. Indicative of the algorithm accuracy we find that 58.6% of these candidate genes were also found in Cancer Census Gene (CGC) list, and 66.2% were found within the PCAWG cancer driver list. We then applied it to identify 30 putative cancer-associated genes that are enriched for synonymous mutations within the same samples. One of the promising gene candidates is the B cell lymphoma 2 (BCL-2) gene. BCL-2 regulates apoptosis by antagonizing the action of proapoptotic BCL-2 family member proteins. The synonymous mutations in BCL2 are enriched in its anti-apoptotic domain and likely play a role in cancer cell proliferation. Our study introduces MutSigCVsyn, an algorithm that accounts for mutational heterogeneity at patient, histology, and gene levels, to identify cancer-associated genes that are enriched for synonymous mutations using whole genome sequencing data. We identified 30 putative candidate genes that will benefit from future experimental studies on the role of synonymous mutations in cancer biology. The online version contains supplementary material available at 10.1186/s12859-023-05521-8.
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影响因子：
--
作者：
Glaser AP;Fantini D;Wang Y;Yu Y;Rimar KJ;Podojil JR;Miller SD;Meeks JJ
通讯作者：
Meeks JJ
DOI：
10.1007/s10555-017-9725-6
发表时间：
2018-03
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Hankey W;Frankel WL;Groden J
通讯作者：
Groden J
影响因子：
9.9
作者：
Bentele, Kajetan;Saffert, Paul;Bluethgen, Nils
通讯作者：
Bluethgen, Nils
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.5
作者：
Daniel DC;Johnson EM
通讯作者：
Johnson EM