Leveraging new methods for comprehensive characterization of mitochondrial DNA in esophageal squamous cell carcinoma

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Xuehan Zhuang, Rui Ye, Yong Zhou, Matthew Yibo Cheng, Heyang Cui, Longlong Wang, Shuangping Zhang, Shubin Wang, Yongping Cui, Weimin Zhang
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Abstract

Mitochondria play essential roles in tumorigenesis; however, little is known about the contribution of mitochondrial DNA (mtDNA) to esophageal squamous cell carcinoma (ESCC). Whole-genome sequencing (WGS) is by far the most efficient technology to fully characterize the molecular features of mtDNA; however, due to the high redundancy and heterogeneity of mtDNA in regular WGS data, methods for mtDNA analysis are far from satisfactory. Here, we developed a likelihood-based method dMTLV to identify low-heteroplasmic mtDNA variants. In addition, we described fNUMT, which can simultaneously detect non-reference nuclear sequences of mitochondrial origin (non-ref NUMTs) and their derived artifacts. Using these new methods, we explored the contribution of mtDNA to ESCC utilizing the multi-omics data of 663 paired tumor-normal samples. dMTLV outperformed the existing methods in sensitivity without sacrificing specificity. The verification using Nanopore long-read sequencing data showed that fNUMT has superior specificity and more accurate breakpoint identification than the current methods. Leveraging the new method, we identified a significant association between the ESCC overall survival and the ratio of mtDNA copy number of paired tumor-normal samples, which could be potentially explained by the differential expression of genes enriched in pathways related to metabolism, DNA damage repair, and cell cycle checkpoint. Additionally, we observed that the expression of CBWD1 was downregulated by the non-ref NUMTs inserted into its intron region, which might provide precursor conditions for the tumor cells to adapt to a hypoxic environment. Moreover, we identified a strong positive relationship between the number of mtDNA truncating mutations and the contribution of signatures linked to tumorigenesis and treatment response. Our new frameworks promote the characterization of mtDNA features, which enables the elucidation of the landscapes and roles of mtDNA in ESCC essential for extending the current understanding of ESCC etiology. dMTLV and fNUMT are freely available from https://github.com/sunnyzxh/dMTLV and https://github.com/sunnyzxh/fNUMT , respectively.
利用新方法全面描述食管鳞状细胞癌线粒体 DNA 的特征
线粒体在肿瘤发生过程中起着至关重要的作用;然而,人们对线粒体DNA(mtDNA)在食管鳞状细胞癌(ESCC)中的作用却知之甚少。全基因组测序(WGS)是迄今为止全面描述 mtDNA 分子特征最有效的技术;然而,由于常规 WGS 数据中 mtDNA 的高度冗余性和异质性,mtDNA 分析方法远不能令人满意。在此,我们开发了一种基于似然法的方法 dMTLV,用于鉴定低质外 mtDNA 变异。此外,我们还介绍了 fNUMT,它可以同时检测线粒体来源的非参考核序列(非参考 NUMTs)及其衍生的伪影。使用这些新方法,我们利用 663 份肿瘤与正常人配对样本的多组学数据探讨了 mtDNA 对 ESCC 的贡献。利用 Nanopore 长读程测序数据进行的验证表明,与现有方法相比,fNUMT 具有更高的特异性和更准确的断点识别能力。利用这种新方法,我们发现 ESCC 的总生存率与配对肿瘤-正常样本的 mtDNA 拷贝数比值之间存在显著关联,这可能是由于新陈代谢、DNA 损伤修复和细胞周期检查点相关通路中富集基因的不同表达所致。此外,我们还观察到,CBWD1 的表达因插入其内隐子区的非参考 NUMTs 而下调,这可能为肿瘤细胞适应缺氧环境提供了前体条件。此外,我们还发现,mtDNA截断突变的数量与肿瘤发生和治疗反应相关特征的贡献之间存在密切的正相关关系。我们的新框架促进了mtDNA特征的表征,从而能够阐明mtDNA在ESCC中的景观和作用,这对扩展目前对ESCC病因学的理解至关重要。dMTLV和fNUMT可分别从 https://github.com/sunnyzxh/dMTLV 和 https://github.com/sunnyzxh/fNUMT 免费获取。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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