Molecular concepts analysis links tumors, pathways, mechanisms, and drugs

Abstract

Global molecular profiling of cancers has shown broad utility in delineating pathways and processes underlying disease, in predicting prognosis and response to therapy, and in suggesting novel treatments. To gain further insights from such data, we have integrated and analyzed a comprehensive collection of "molecular concepts" representing > 2500 cancer-related gene expression signatures from Oncomine and manual curation of the literature, drug treatment signatures from the Connectivity Map, target gene sets from genome-scale regulatory motif analyses, and reference gene sets from several gene and protein annotation databases. We computed pairwise association analysis on all 13,364 molecular concepts and identified > 290,000 significant associations, generating hypotheses that link cancer types and subtypes, pathways, mechanisms, and drugs. To navigate a network of associations, we developed an analysis platform, the Molecular Concepts Map. We demonstrate the utility of the approach by highlighting molecular concepts analyses of Myc pathway activation, breast cancer relapse, and retinoic acid treatment.

Figure 1

The MCM project. (A) Molecular concepts or biologically related gene sets were collected, standardized, and stored in the MCM database. Molecular concepts were derived from 503 independent microarray studies comprising > 20,000 microarray experiments, 3 promoter scanning and comparative genomics regulatory motif analyses, and 12 gene and protein annotation resources (Table 1). Molecular concepts were standardized to Entrez Gene identifiers. Each pair of molecular concepts was compared and assessed for significant association with Fisher's exact test. Pairs of concepts that exhibited statistically significant overlap (P < 1e − 6) were considered “linked.” A database-driven web application (http://www.oncomine.org) was developed to analyze and visualize molecular concepts and concept links. The web application also serves as a portal for users to upload and analyze new concepts. (B) An overview of concept types represented in the analysis. Table 1 provides exact concept counts. (C) Pairwise association analysis of all molecular concepts identified 322,656 pairs of significantly linked concepts. The area of each circle is proportional to the number of significant associations between pairs of concept types.

Figure 2

Molecular concepts analysis of the Myc pathway activation signature, consisting of the top 5% of genes most overexpressed in Myc transfection in human mammary epithelial cells [24]. (A) A molecular concepts map of the Myc signature (red node) and selected significantly linked concepts. Each node represents a molecular concept or a set of biologically related genes. The size of the node is proportional to the number of genes in the concept. The color of the concept indicates concept type (see legend). Each edge signifies a statistically significant association (P < 1e − 6). The drug signatures consist of genes downregulated by drug treatment in the specified cell line. HMECs = human mammary epithelial cells. Concept details are provided in Table W1. (B) Representative heatmaps depicting Myc pathway activation in Ig-Myc-positive lymphoma, metastatic prostate cancer, colorectal carcinoma, and grade III breast cancer. Each heatmap column is an individual tumor. Each row is a gene from the Myc activation signature. Red and blue indicate relative overexpression and underexpression, respectively. Ig-Myc = Myc translocation involving immunoglobulin locus; DLBCL = diffuse large B-cell lymphoma; B-UC = B-cell lymphoma unclassified; BL = Burkitt's lymphoma; Met = metastatic prostate cancer; BCa = breast carcinoma. (C) Representative heatmaps depicting Myc pathway repression by LY-294002 and wortmannin treatments.

Figure 3

Molecular concepts analysis of an ER⁺ breast cancer relapse signature (MCM: 122567) consisting of the top 5% of genes most overexpressed in ER⁺ tumors from patients who relapsed within 5 years relative to those who did not. (A) A molecular concepts map of the ER⁺ relapse signature (yellow node) and selected significantly linked concepts. Each node represents a molecular concept or a set of biologically related genes. The size of the node is proportional to the number of genes in the concept. The color of the concept indicates concept type (see legend). Each edge signifies a statistically significant association (P < 1e − 6). The drug signatures consist of genes downregulated by drug treatment in the specified cell line. HMECs = human mammary epithelial cells. Concept details are provided in Table W2. (B) Representative heatmaps depicting the expression of cell cycle, serum response, and 17q25 concepts in the dataset from which the ER⁺ relapse signature was derived. Each heatmap column is an individual ER⁺ breast tumor. Each row is a gene from the ER⁺ relapse signature and denoted concepts. Red and blue indicate relative overexpression and underexpression, respectively.

Figure 4

Molecular concepts analysis of a retinoic acid signature, consisting of 454 genes repressed in APL cells treated with retinoic acid. (A) A molecular concepts map of the retinoic acid signature (yellow node) and selected significantly linked concepts. Each node represents a molecular concept or a set of biologically related genes. The size of the node is proportional to the number of genes in the concept. The color of the concept indicates concept type (see legend). Each edge signifies a statistically significant association (P < 1e − 6). The drug signatures consist of genes downregulated by drug treatment in the specified cell line. HMECs = human mammary epithelial cells; AML = acute myeloid leukemia; ALL = acute lymphoblastic leukemia. Concept details are provided in Table W4. (B) A heatmap depicting genes from the retinoic acid signature in an AML dataset from which an M3 (APL) signature was derived. Each heatmap column is an individual AML specimen. Each row is a gene from the retinoic acid signature. Red and blue indicate relative overexpression and underexpression, respectively.