SynLethDB 2.0: A web-based knowledge graph database on synthetic lethality for novel anticancer drug discovery

Abstract

Two genes are synthetic lethal if mutations in both genes result in impaired cell viability, while mutation of either gene does not affect the cell survival. The potential usage of synthetic lethality (SL) in anticancer therapeutics has attracted many researchers to identify synthetic lethal gene pairs. To include newly identified SLs and more related knowledge, we present a new version of the SynLethDB database to facilitate the discovery of clinically relevant SLs. We extended the first version of SynLethDB database significantly by including new SLs identified through CRISPR screening, a knowledge graph about human SLs, and new web interface, etc. Over 16,000 new SLs and 26 types of other relationships have been added, encompassing relationships among 14,100 genes, 53 cancers, and 1,898 drugs, etc. Moreover, a brand-new web interface has been developed to include modules such as SL query by disease or compound, SL partner gene set enrichment analysis and knowledge graph browsing through a dynamic graph viewer. The data can be downloaded directly from the website or through the RESTful APIs. The database is accessible online at http://synlethdb.sist.shanghaitech.edu.cn/v2.

SLIDE-VIP: a comprehensive, cell line- and patient-based framework for synthetic lethality prediction in DNA damage repair, chromatin remodeling and cell cycle

“…We next selected one pair of particular interest from the top candidates for the focus SL gene pairs, namely the PRKDC and ATM pair (Figure 2). This pair has confirmed SL potential according to the SynLethDBv2.0 database [56]. The waterfall plot of ATM dependency in cell line knock-out screens shows enrichment of negative dependency scores in cell lines with PRKDC LoF (red bars in Figure 2A).…”

“…Several synthetic lethal interactions between the focus genes found by using SLIDE-VIP have already been identified previously, thus confirming the validity of our approach. Among the top 683 focus pairs, 30 are featured in the SynLethDBv2.0 database [56]. This is a very significant enrichment (p-value 7.5 × 10 −63 ; hyper-geometric test with the assumption of 200 mln possible gene pairs and 37 thousand being featured in Syn-LethDBv2.0).…”

“…Thus, the focus vs druggable test series is more exploratory and intended to provide candidates for drug repurposing. For the top 200 focus vs druggable pairs, four were also found in SynLethDBv2.0 database [56]. This is still a significant enrichment (p-value 5.3 × 10 −10 ) measured with a hypergeometric test with the assumption of 200 mln possible gene pairs and 37 thousand being synthetic lethal (the number of records in SynLethDBv2.0).…”

A heuristic algorithm solving the mutual-exclusivity-sorting problem

“…To extend the comparison between the MutExMatSoring and MEMo algorithms, we compared their ability to recapitulate known SL gene pairs ( Fig. 6 ) derived from the SynLethDBv2 database ( Wang et al , 2022 ) on a binary dependency dataset derived from Project Score ( Dwane et al , 2021 ). In this dataset, a non-zero entry in the position [ i, j ] corresponds to an observed reduction of viability of the cell line j , upon CRISPR-cas9 knock-out of gene i , i.e.…”

“…We considered known human SL pairs ( Wang et al , 2022 ) with a quantitative score greater than 0.4 across four cancer types: breast carcinoma, colorectal carcinoma, LUAD and OV carcinoma. The confidence score of an SL pair is given by a weighted aggregation of different sources of evidence (e.g.…”