MDP (Mutations and Drugs Portal): a database that links genomics to pharmacological data

Introduction

The Mutations and Drugs Portal (MDP) is a public accessible database that interconnects pharmacological information extracted from the NCI60 DTP screening with genomic data of the CCLE and NCI60 projects that has been designed with the aim to develop novel targeted therapies by identifying cancer cells with specific drug sensitivity as a result of genetic abnormalities. The MDP database builds on exome-sequencing and drug response data from the NCI60 and the CCLE datasets. Specifically, the MDP database not only associates pharmacological and genomics data of the NCI60 repository but also correlates CCLE sequencing data (1,651 genes) to NCI60 drug response information (50,816 compound). The guiding element, used to link NCI60 pharmacological information to CCLE and NCI60 genomic data, is the set of common cancer cell lines between the NCI60 drug screening (now available for 115 cell lines) and the CCLE and NCI60 genomic repositories, comprising 50 and 60 cell lines, respectively. Using these common cell lines, MDP can query NCI60 pharmacological data and CCLE and NCI-60 genomic information to identify drugs correlated to gene mutations (From Gene to Drug) or gene mutations associated to drug response (From Drug to Gene).

Methods

Statistical analyses are based on the drug response data file GI50 Data (Sept 2014 release) , retrieved from the NCI60 DTP portal, and sequencing data and variant classifications retrieved from the CCLE and NCI60 public repositories. GI50 Data file contains a matrix of GI50 values which are computed, for any compound, as minus the log10 of IC50, i.e., the drug concentration necessary to inhibit 50% growth of treated cells relative to untreated controls. Prior to analysis, for any single compound, first the GI50 is transformed back to IC50 and then the IC50 value is normalized dividing the IC50 of any cell line by the average of the IC50 across all the cell lines. The normalized IC50 (in log2 scale) of a compound is used to define the response for any combination of drug and cell line in terms of i) good response if the normalized log2 IC50 is lower than two standard deviations of the distribution of all log2 IC50 in a given cell line, and ii) bad response otherwise.

NCI60 and CCLE

The DTP NCI 60 Human Tumor Cell Line Screen checks thousands of compounds for evidence of the ability to inhibit the growth of human tumor cell lines and also provides genomic information for cancer cell lines used during test experiments. The Cancer Cell Line Encyclopedia conducted a detailed genetic and pharmacologic characterization of a large panel of human cancer cell lines. Both CCLE and NCI-60 provide public access to Next Generation Sequencing genomic data (Exome-Sequencing), gene expression analysis data and more. Moreover, we implemented the option to investigate either NCI60 or CCLE database, which differ each other for the number of genes and SNPs.

Queries

When selecting the From Gene to Drug section, both run analysis on CCLE and run analysis on NCI60 buttons re-direct to a web page where the user can query for the gene names or the SNP Ids of interest. Multiple gene names or dbSNP Ids can be inputted at the same time to explore drug sensitivity to combinations of multiple genes or SNPs. Once selected the genomic entity, the query can be limited to subsets of tissues (i.e., cell lines) and of variant classifications (i.e., mutation types). Instead, when using the From Drug to Gene analysis, MDP identifies genomic variants that might be related to the sensitivity or resistance of cancer cell lines to a specific queried compound. Results in both analyses are returned using graphical and interactive representations and the list of molecules can be downloaded for post-processing evaluations.

In order to use the application click the button below and follow the on-screen instruction.