Dataset Information

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

ABSTRACT: The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.

SUBMITTER: Ikediobi ON

PROVIDER: S-EPMC2705832 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

Ikediobi Ogechi N ON Davies Helen H Bignell Graham G Edkins Sarah S Stevens Claire C O'Meara Sarah S Santarius Thomas T Avis Tim T Barthorpe Syd S Brackenbury Lisa L Buck Gemma G Butler Adam A Clements Jody J Cole Jennifer J Dicks Ed E Forbes Simon S Gray Kristian K Halliday Kelly K Harrison Rachel R Hills Katy K Hinton Jonathan J Hunter Chris C Jenkinson Andy A Jones David D Kosmidou Vivienne V Lugg Richard R Menzies Andrew A Mironenko Tatiana T Parker Adrian A Perry Janet J Raine Keiran K Richardson David D Shepherd Rebecca R Small Alex A Smith Raffaella R Solomon Helen H Stephens Philip P Teague Jon J Tofts Calli C Varian Jennifer J Webb Tony T West Sofie S Widaa Sara S Yates Andy A Reinhold William W Weinstein John N JN Stratton Michael R MR Futreal P Andrew PA Wooster Richard R

Molecular cancer therapeutics 20061106 11

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 ...[more]

PMID: 17088437

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Project description:Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.

Dataset Information

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

Publications

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

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