title: 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.
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; HiThru Analytics LLC, Laurel, Maryland, United States of America.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica, Programa de Pós-Graduação em Farmácia, Universidade Federal de Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Fabricio
authors.initials: F
authors.lastname: Sousa
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; SRA International, Fairfax, Virginia, United States of America.
authors.forename: Margot
authors.initials: M
authors.lastname: Sunshine
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ogan D
authors.initials: OD
authors.lastname: Abaan
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Davis
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Spencer W
authors.initials: SW
authors.lastname: Reinhold
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
authors.affiliation: Developmental Therapeutic Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Developmental Therapeutic Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Developmental Therapeutic Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual; D059472:Exome / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D016678:Genome / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000970:Antineoplastic Agents