title: The NCI-60 Methylome and Its Integration into CellMiner.
abstract: A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (∼21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and miRNA transcripts, DNA copy number, and protein levels. Here, we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2.0 (https://discover.nci.nih.gov/cellminer). Among new insights, transcript versus DNA methylation correlations revealed the epithelial/mesenchymal gene functional category as being influenced most heavily by methylation. DNA methylation and copy number integration with transcript levels yielded an assessment of their relative influence for 15,798 genes, including tumor suppressor, mitochondrial, and mismatch repair genes. Four forms of molecular data were combined, providing rationale for microsatellite instability for 8 of the 9 cell lines in which it occurred. Individual cell line analyses showed global methylome patterns with overall methylation levels ranging from 17% to 84%. A six-gene model, including PARP1, EP300, KDM5C, SMARCB1, and UHRF1 matched this pattern. In addition, promoter methylation of two translationally relevant genes, Schlafen 11 (SLFN11) and methylguanine methyltransferase (MGMT), served as indicators of therapeutic resistance or susceptibility, respectively. Overall, our database provides a resource of pharmacologic data that can reinforce known therapeutic strategies and identify novel drugs and drug targets across multiple cancer types. Cancer Res; 77(3); 601-12. ©2016 AACR.
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. wcr@mail.nih.gov pommier@nih.gov.
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.|Systems Research and Applications Corp., Fairfax, Virginia.|HiThru Analytics LLC, Laurel, Maryland.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.|Systems Research and Applications Corp., Fairfax, Virginia.
authors.forename: Margot
authors.initials: M
authors.lastname: Sunshine
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Rajapakse
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Augustin
authors.initials: A
authors.lastname: Luna
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
authors.affiliation: Genetics Branch, Developmental Therapeutic Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Holly
authors.initials: H
authors.lastname: Stevenson
authors.affiliation: Genetics Branch, Developmental Therapeutic Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Nogales
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Office of the Director, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Goldstein
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.|Divison of Cancer Treatment and Diagnosis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Genetics Branch, Developmental Therapeutic Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. wcr@mail.nih.gov pommier@nih.gov.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D016208:Databases, Factual; D006801:Humans; D020407:Internet; D009369:Neoplasms / Q000235:genetics*