Dataset Information

NCI-60 whole exome sequencing and pharmacological CellMiner analyses.

ABSTRACT: Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in cancer progression and differential drug response were identified for 2,546 genes. Potential gene knockouts are made available. Assessment of cell line response to 19,940 compounds, including 110 FDA-approved drugs, reveals ?80-fold range in resistance versus sensitivity response across cell lines. 103,422 gene variants were significantly correlated with at least one compound (at p<0.0002). These include genes of known pharmacological importance such as IGF1R, BRAF, RAD52, MTOR, STAT2 and TSC2 as well as a large number of candidate genes such as NOM1, TLL2, and XDH. We introduce two new web-based CellMiner applications that enable exploration of variant-to-compound relationships for a broad range of researchers, especially those without bioinformatics support. The first tool, "Genetic variant versus drug visualization", provides a visualization of significant correlations between drug activity-gene variant combinations. Examples are given for the known vemurafenib-BRAF, and novel ifosfamide-RAD52 pairings. The second, "Genetic variant summation" allows an assessment of cumulative genetic variations for up to 150 combined genes together; and is designed to identify the variant burden for molecular pathways or functional grouping of genes. An example of its use is provided for the EGFR-ERBB2 pathway gene variant data and the identification of correlated EGFR, ERBB2, MTOR, BRAF, MEK and ERK inhibitors. The new tools are implemented as an updated web-based CellMiner version, for which the present publication serves as a compendium.

SUBMITTER: Reinhold WC

PROVIDER: S-EPMC4102467 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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NCI-60 whole exome sequencing and pharmacological CellMiner analyses.

Reinhold William C WC Varma Sudhir S Sousa Fabricio F Sunshine Margot M Abaan Ogan D OD Davis Sean R SR Reinhold Spencer W SW Kohn Kurt W KW Morris Joel J Meltzer Paul S PS Doroshow James H JH Pommier Yves Y

PloS one 20140717 7

Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in can ...[more]

PMID: 25032700

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Project description:CellMiner (http://discover.nci.nih.gov/cellminer) and CellMinerCDB (https://discover.nci.nih.gov/cellminercdb/) are web-based applications for mining publicly available genomic, molecular, and pharmacologic datasets of human cancer cell lines including the NCI-60, Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, Cancer Therapeutics Response Portal, NCI/DTP small cell lung cancer, and NCI Almanac cell line sets. Here, we introduce our RNA sequencing (RNA-seq) data for the NCI-60 and their access and integration with the other databases. Correlation to transcript microarray expression levels for identical genes and identical cell lines across CellMinerCDB demonstrates the high quality of these new RNA-seq data. We provide composite and isoform transcript expression data and demonstrate diversity in isoform composition for individual cancer- and pharmacologically relevant genes, including HRAS, PTEN, EGFR, RAD51, ALKBH2, BRCA1, ERBB2, TP53, FGFR2, and CTNND1. We reveal cell-specific differences in the overall levels of isoforms and show their linkage to expression of RNA processing and splicing genes as well as resultant alterations in cancer and pharmacologic gene sets. Gene-drug pairings linked by pathways or functions show specific correlations to isoforms compared with composite gene expression, including ALKBH2-benzaldehyde, AKT3-vandetanib, BCR-imatinib, CDK1 and 20-palbociclib, CASP1-imexon, and FGFR3-pazopanib. Loss of MUC1 20 amino acid variable number tandem repeats, which is used to elicit immune response, and the presence of the androgen receptor AR-V4 and -V7 isoforms in all NCI-60 tissue of origin types demonstrate translational relevance. In summary, we introduce RNA-seq data to our CellMiner and CellMinerCDB web applications, allowing their exploration for both research and translational purposes. SIGNIFICANCE: The current study provides RNA sequencing data for the NCI-60 cell lines made accessible through both CellMiner and CellMinerCDB and is an important pharmacogenomics resource for the field.

Project description:BACKGROUND & AIMS:A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS:We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS:Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS:Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.

Dataset Information

NCI-60 whole exome sequencing and pharmacological CellMiner analyses.

Publications

NCI-60 whole exome sequencing and pharmacological CellMiner analyses.

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