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

Li Guo; Sunjing Li; Bowen Qian; Youquan Wang; Rui Duan; Wenwen Jiang; Yihao Kang; Yuyang Dou; Guowei Yang; Lulu Shen; Jun Wang; Tingming Liang

doi:10.1016/j.csbj.2020.10.015

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

Comput Struct Biotechnol J. 2020 Oct 21:18:3243-3254. doi: 10.1016/j.csbj.2020.10.015. eCollection 2020.

Authors

Li Guo¹, Sunjing Li¹, Bowen Qian¹, Youquan Wang¹, Rui Duan², Wenwen Jiang¹, Yihao Kang¹, Yuyang Dou¹, Guowei Yang¹, Lulu Shen², Jun Wang¹, Tingming Liang^{2

3}

Affiliations

¹ Department of Bioinformatics, Smart Health Big Data Analysis and Location Services Engineering Lab of Jiangsu Province, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, China.
² Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China.
³ Changzhou Institute of Innovation and Development, Nanjing Normal University, Nanjing 210023, China.

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.

Keywords: ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; Cancer therapy; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; Pan-cancer analysis; READ, rectum adenocarcinoma; RNA interaction; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; Synthetic lethality; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; TSG, tumor suppressor gene; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.