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Integrative omics analysis reveals relationships of genes with synthetic lethal interactions through a pan-cancer analysis.

ABSTRACT: Synthetic lethality is thought to play an important role in anticancer therapies. Herein, to understand the potential distributions and relationships between synthetic lethal interactions between genes, especially for pairs deriving from different sources, we performed an integrative analysis of genes at multiple molecular levels. Based on inter-species phylogenetic conservation of synthetic lethal interactions, gene pairs from yeast and humans were analyzed; a total of 37,588 candidate gene pairs containing 7,816 genes were collected. Of these, 49.74% of genes had 2-10 interactions, 22.93% were involved in hallmarks of cancer, and 21.61% were identified as core essential genes. Many genes were shown to have important biological roles via functional enrichment analysis, and 65 were identified as potentially crucial in the pathophysiology of cancer. Gene pairs with dysregulated expression patterns had higher prognostic values. Further screening based on mutation and expression levels showed that remaining gene pairs were mainly derived from human predicted or validated pairs, while most predicted pairs from yeast were filtered from analysis. Genes with synthetic lethality were further analyzed with their interactive microRNAs (miRNAs) at the isomiR level which have been widely studied as negatively regulatory molecules. The miRNA-mRNA interaction network revealed that many synthetic lethal genes contributed to the cell cycle (seven of 12 genes), cancer pathways (five of 12 genes), oocyte meiosis, the p53 signaling pathway, and hallmarks of cancer. Our study contributes to the understanding of synthetic lethal interactions and promotes the application of genetic interactions in further cancer precision medicine.

SUBMITTER: Guo L

PROVIDER: S-EPMC7658657 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Integrative omics analysis reveals relationships of genes with synthetic lethal interactions through a pan-cancer analysis.

Guo Li L Li Sunjing S Qian Bowen B Wang Youquan Y Duan Rui R Jiang Wenwen W Kang Yihao Y Dou Yuyang Y Yang Guowei G Shen Lulu L Wang Jun J Liang Tingming T

Computational and structural biotechnology journal 20201021

Synthetic lethality is thought to play an important role in anticancer therapies. Herein, to understand the potential distributions and relationships between synthetic lethal interactions between genes, especially for pairs deriving from different sources, we performed an integrative analysis of genes at multiple molecular levels. Based on inter-species phylogenetic conservation of synthetic lethal interactions, gene pairs from yeast and humans were analyzed; a total of 37,588 candidate gene pai ...[more]

PMID: 33240468

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Project description:BackgroundCancer cells undergo various rewiring of metabolism and dysfunction of epigenetic modification to support their biosynthetic needs. Although the major features of metabolic reprogramming have been elucidated, the global metabolic genes linking epigenetics were overlooked in pan-cancer.ObjectivesIdentifying the critical metabolic signatures with differential expressions which contributes to the epigenetic alternations across cancer types is an urgent issue for providing the potential targets for cancer therapy.MethodThe differential gene expression and DNA methylation were analyzed by using the 5726 samples data from the Cancer Genome Atlas (TCGA).ResultsFirstly, we analyzed the differential expression of metabolic genes and found that cancer underwent overall metabolism reprogramming, which exhibited a similar expression trend with the data from the Gene Expression Omnibus (GEO) database. Secondly, the regulatory network of histone acetylation and DNA methylation according to altered expression of metabolism genes was summarized in our results. Then, the survival analysis showed that high expression of DNMT3B had a poorer overall survival in 5 cancer types. Integrative altered methylation and expression revealed specific genes influenced by DNMT3B through DNA methylation across cancers. These genes do not overlap across various cancer types and are involved in different function annotations depending on the tissues, which indicated DNMT3B might influence DNA methylation in tissue specificity.ConclusionsOur research clarifies some key metabolic genes, ACLY, SLC2A1, KAT2A, and DNMT3B, which are most disordered and indirectly contribute to the dysfunction of histone acetylation and DNA methylation in cancer. We also found some potential genes in different cancer types influenced by DNMT3B. Our study highlights possible epigenetic disorders resulting from the deregulation of metabolic genes in pan-cancer and provides potential therapy in the clinical treatment of human cancer.

Dataset Information

Integrative omics analysis reveals relationships of genes with synthetic lethal interactions through a pan-cancer analysis.

Publications

Integrative omics analysis reveals relationships of genes with synthetic lethal interactions through a pan-cancer analysis.

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