In the present study, copy number alterations (CNAs), mutation and expression profiles of 8580 samples were integrated across 32 cancer types from The Cancer Genome Atlas (TCGA) to identify co-occurrence and mutual exclusivity gene pairs (Figure A, B). Reliable co-occurrence and mutual exclusivity interactions were then selected from functional screening data, including shRNA and CRISPR datasets (Figure C). The strategy was based on the notion that knockdown of one gene causes a selective enhancement (synthetic viability) or reduction (synthetic lethality) in cell viability with simultaneous alterations in another gene. In addition, the positive and negative interactions in yeast genetic interactions were also used to infer SV and SL relationships, respectively, in human cancer cells. Ultimately, the co-occurrence and mutual exclusivity gene pairs verified in at least one type of dataset (shRNA, CRISPR or yeast) were selected as candidate genetic interactions (Figure C). SV and SL interactions were validated by (1) showing expected drug response detected by four pharmacogenomic datasets (Figure D) as well as (2) observing worse survival of patients with alterations in SV interactions and better survival of patients with alterations in SL interactions in the prognosis analysis (Figure E). Moreover, network analysis and pathway enrichment analysis were performed to investigate the functional relationship between genes with genetic interactions. The biomarkers identified by the present work will contribute to predict the mechanism of drug resistance or sensitivity in clinical application and will guide precise targeting of existing therapies.
>
The statistic of synthetic lethality gene pairs from other researches:
Study and Reference Data of Publication Total Number Method
SynlethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets. Nuclie Acids Res, 2016-1 19952 DAISY/DECIPHER/Text Mining/RNAi/Synlethality
Ranking novel cancer driving synthetic lethal gene pairs using TCGA data. Oncotarget, 2016-8 128 Mutation exclusivity
Identification of potential synthetic lethal genes to p53 using a computational biology approach. BMC Med Genomics, 2013-9 93 Expression
Identification of synthetic lethal pairs in biological systems through network information centrality. Mol Biosyst, 2013-8 109 Network
Inferring synthetic lethal interactions from mutual exclusivity of genetic events in cancer. Biol Direct, 2015-10 813 Mutation exclusivity
A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. Mol Cell, 2016-8 5556 Network
Genetic interaction mapping in mammalian cells using CRISPR interference. Nat Methods, 2017-6 109 CRISPR
Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions. Nat Methods, 2017-6 181 CRISPR
Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat Biotechnol, 2017-5 38 CRISPR
Therapeutic relevance of the protein phosphatase 2A in cancer. Oncotarget, 2016-9 464 DAISY
Multi-omic measurement of mutually exclusive loss-of-function enriches for candidate synthetic lethal gene pairs. BMC Genomics, 2016-1 978 Mutation exclusivity
Connectivity Homology Enables Inter-Species Network Models of Synthetic Lethality. PLoS Comput Biol, 2015-10 1492 connectivity-homology-based models
Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types. Mol Syst Biol, 2015-7 22 permut
A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities. Mol Syst Biol, 2013-10 204 shRNA
Mapping genetic interactions in human cancer cells with rnAi and multiparametric phenotyping. Nat Methods, 2013-5 224 RNAi
Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens. biorxiv, 2017-3 57 CRISPR
1.How to cite CGIdb?
2.Where do the datasets come from?
We obtained multidimensional genomics data across 32 cancer types from the TCGA consortium, including mutation, copy number and expression data. The mutation and copy number data for cell lines are obtained from the CCLE and GDSC resource.

(1) Mutation, copy number alterations and expression profiles are derived across 32 cancer types from TCGA consortium, including 8580 patient samples.

(2) ShRNA data were downloaded from The Project Achilles database, which provides shRNA depletion scores from pooled genomic library tests across 216 cancer cell lines.

(3) High-throughput CRISPR-Cas9 screening data, including 63 cancer cell lines, were downloaded from the GenomeCRISPR database.

(4) A genome-scale genetic interaction map in yeast was obtained from Costanzo et al. (Costanzo M, Baryshnikova A, Bellay J et al. The genetic landscape of a cell. Science 2010; 327: 425-31.).

(5) The original pharmacological screening data were downloaded from Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), Broad Cancer Therapeutics Response Portal (CTRP, http://www.broadinstitute.org/ctrp/) and NCI60.

(6) Synthetic viable or synthetic lethal interactions were integrated from 17 studies (Table 1)

Table 1. Statistics of the SV and SL interactions from other studies

Source (PMID) SL SV
27438146 107
26427375 843
27453043 5065
24025726 98
23728082 100
26516187 19952
24104479 200
26227665 23 40
28319113 168 10
26451775 1309
Boettcher et al. 57 80
28481362 95 178
26781748 846
27557495 464
23563794 211 199
28319085 30
3.How to use the CGIdb? 
3.1 Search
In the Search page, users can key in gene ID or symbol to perform a search of corresponding genetic interactions (1), which can be further screened by advance options (2-3).
3.2 Search Results
When user queries the genes to the database, the CGIdb will provide search results on this page. The search results are divided into two main parts: (i) information box, which includes the basic information of your selected gene, and the external link to NCBI for more detail (1); (ii) The SL/SV pairs list is provided on the bottom of page (2). And user can click the button (3) to view the details of the gene pairs, including drugs effect and protein-protein interaction network. The results can be exported as CSV format (4).
3.3 Search Details
The details of results are divided in three parts. (i) Distribution of gene alteration in TCGA data are provided. CGIdb shows the altered samples (mutation and copy number alteration) of genes and statistic of analysis results (1-2). (ii) In the middle of page, user can get results of the drug effect. In cell lines with drug targeting the searching gene, a one-sided Wilcoxon rank sum test is used to test whether the drug response measures, such as IC50, are significantly higher or lower in cells lines with and without alterations of the partner genes in the genetic interaction (3). Detailed information about the pharmacodynamic data are shown in the right table (4-5). (iii) On the bottom of the detail page, CGIdb provides the visualized network of protein-protein interactions derived from PathwayCommon. User can export network as jpg or png file (6-7).
3.4 Browse
In the Browse page, users can easily filter SV and SL pairs classified by tissue types. The human body on the left includes optional tissue types (1). Click on the tissue on the model to filter the genetic interactions of the tissue. The detailed results are showed in the right table (2).
3.5 Data
In the data page, users can download or upload data, We provide all SV and SL pairs, which are classified by different sources and tissue types (1-3).
4.How should I interpret the Score ?
The SV and SL interactions analyzed in the present study were obtained from different types of sources, including computational predictions, biochemical assays, and text mining results. In addition, biochemical assays were based on different experimental technologies and platforms, such as shRNA, CRISPR and drug inhibition. Because multiple types of evidence are conducive to the identification of SV (SL) interactions, an integrative confidence score combining scores from these evidence sources can provide an overall estimation of the reliability of a SV (SL) interaction. In principle, we supposed that (i) the contribution of experimental evidence to the confidence score is more significant than the contribution of predictive algorithms or text mining and that (ii) the SV (SL) interactions supported by more evidence sources should be beneficial to the confidence score. The scoring procedures were divided into two steps, i.e., quantification and integration. A large number of SV (SL) interactions collected from other studies had only qualitative annotation evidence (such as “high-throughput” or “low-throughput”), or technological descriptions of wet-lab experiments (such as “CRISPR screening” or “shRNA screening”). Thus, it was necessary to assign quantitative scores to these SV (SL) interactions before the calculation of integrative scores. Similar to the scoring scheme from SLDB, the quantitative scores were assigned based on the experimental methods as shown in the following Table 2. For instance, “Mutant & Mutant” indicated that the pair of SV (SL) genes were disturbed by transgenic or genetic deletions. Moreover, “RNA interference & Mutant” indicated that one gene was perturbed by RNAi and that the other was perturbed via mutation. In summary, the SV (SL) interactions obtained from low-throughput experiments were considered to be more reliable than the results from high-throughput experiments due to the lower false positive rate. However, a higher confidence score was assigned to low-throughput evidence than high-throughput evidence. Compared to other RNA interference experiments (such as shRNA, siRNA and dsRNA), the CRISPR screen had lower off-target effects, which were assigned higher confidence scores similar to mutation and transfection experiments (Table 2).

The formula to combine the individual scores as follows:

where s represents the integrative score corresponding to the experimental evidence; pi is the individual score; and n is the total number of experimental supporting evidence.

Table 2. Quantitative scores assigned to SVs and SLs according to the experimental methods annotated in evidence sources

Method Score
Mutant & Mutant 0.9
CRISPR 0.9
Low-throughput 0.8
RNA interference & Mutant 0.75
Bi-specifie RNA interference 0.5
RNA interference & Drug inhibition 0.5
High-throughput 0.5