The NCI-60 Methylome and Its Integration into CellMiner

Area of Science:

• Genomics
• Systems Pharmacology
• Cancer Biology

Background:

• The NCI-60 cancer cell line panel is a vital resource for drug discovery, offering extensive compound and genomic data.
• Existing data lacked comprehensive genome-wide DNA methylation profiles for the NCI-60 panel.

Purpose of the Study:

• To establish the first readily usable genome-wide DNA methylation database for the NCI-60 cancer cell line panel.
• To integrate DNA methylation data with existing genomic and pharmacologic data for novel insights.

Main Methods:

• Utilized the Infinium HumanMethylation450k BeadChip array to generate DNA methylation data for 485,577 probes across the NCI-60 panel.
• Integrated DNA methylation signatures for 17,559 genes into the open-access CellMiner version 2.0 platform.
• Performed correlations between transcript levels and DNA methylation, and integrated DNA methylation with copy number data.

Main Results:

• Identified epithelial/mesenchymal transition gene category as significantly influenced by DNA methylation.
• Assessed the relative influence of DNA methylation and copy number on transcript levels for 15,798 genes.
• Found promoter methylation of SLFN11 and MGMT as indicators of therapeutic resistance and susceptibility, respectively.
• Developed a six-gene model (PARP1, EP300, KDM5C, SMARCB1, UHRF1) correlating with global methylome patterns.

Conclusions:

• The new DNA methylation database provides a valuable resource for systems pharmacology and genomic studies.
• The findings reinforce known therapeutic strategies and highlight potential novel drug targets and therapies for various cancer types.
• This integrated molecular data resource facilitates a deeper understanding of cancer biology and drug response mechanisms.