A functional genomic study on NCI's anticancer drug screen

Abstract

Pharmacogenomics requires massive computer exploration on heterogeneous databases. COMPARE, the gateway to the NCI's anticancer drug screen database, allows users to correlate drug-sensitivity profiles with a functional genomic database. However, most drugs of known molecular mechanism turn out to be uncorrelated with their molecular-target gene expression. Based on a novel statistical concept, liquid association, we develop an on-line system to identify candidate genes that intervene, confound and weaken the drug-gene correlation. The system takes queries and returns button-clickable tables of functionally associated genes for rerouting to knowledgebases such as Locus Link, OMIM and PubMed. We report results that link methotrexate resistance to DNA component biosynthesis, and taxol sensitivity to genes associated with human immunodeficiency virus infection. The drug-sensitivity database can be synergistically coanalyzed with gene expression data to study proteins of poorly understood physiological roles. When applied to the human prion, a cellular context embroidered with the gene expression network of Alzheimer disease is revealed.

Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Previous efforts using this strategy have focused mainly on finding causes of drug resistance. [2][3][4]11,17,18 Gene expression signatures have also been used as surrogate markers of cellular states, for example, to identify agents that induce the differentiation of acute myeloid leukemia cells.…”

Modeling Liquid Association

“…Gene co‐expression relationships often exist specifically under certain biological conditions (Lai et al, 2004; Dettling, Gabrielson, and Parmigiani, 2005; Ho et al, 2007), suggesting that rich models of gene interaction will be crucial to continued advancement. Moreover, several studies have suggested that during a biological process the co‐expression patterns within a set of genes may be modulated by the expression level of one or more additional genes (Li, 2002; Li et al, 2004; Li and Yuan, 2004; Zhang, Ji, and Zhang, 2007). Examination of canonical gene pathways provides additional support for this phenomenon.…”

Prediction of anticancer drug response by transcriptome analysis. The new pathways of pharmacogenomics

“…Toujours dans ces développe-ments bioinformatiques, on peut aussi citer une méthode dénommée « l'association liquide » (liquid association) permettant d'identifier des gènes candidats pouvant interférer avec les corrélations attendues entre la cytotoxicité d'une molécule et l'expression d'un gène cible [14].…”