Comprehensive List of Cancer-Related Genetic Variations of the NCI-60 Panel
Results of whole exome sequencing of the NCI-60 cell lines. Variant counts for each cell line from tumor type are plotted for Type 1 and Type 2 fraction as green squares and red diamonds, respectively. Within each tumor type, the variant counts are sorted from lowest to highest, and a box plot is superimposed to demonstrate subgroup mean and spread.
The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. The panel of cell lines represents nine different types of cancer: breast, ovary, prostate, colon, lung, kidney, brain, leukemia, and melanoma. Originally developed to screen anticancer compounds by the NCI Developmental Therapeutics Program (DTP), the NCI-60 panel has generated the most extensive cancer pharmacology database worldwide. The 60 cell lines have also been extensively analyzed for their gene and microRNA expression levels, DNA mutation status, and DNA copy number variations. These findings have provided the groundwork for research centered on increasing our understanding of tumor biology and drug activity.
Yves Pommier, M.D., Ph.D., and James Doroshow, M.D., in CCR’s Laboratory of Molecular Pharmacology, along with Paul Meltzer, M.D., Ph.D., in CCR’s Genetics Branch, and their colleagues in the CCR and DTP set out to develop a comprehensive list of genetic variants for each cell type that comprises the NCI-60 cell line collection. They conducted whole exome sequencing (WES) on the 60 cell lines to identify novel cancer variants, and then identified pharmacogenomic correlations between the variants and anticancer agents.
The researchers began their studies by extracting DNA from the NCI-60 cells and subjecting it to WES. Using a stringent filtering system, variants were identified and were divided into two groups: Type 1 variants were those found in the normal population and Type 2 variants were most likely to be acquired cancer-specific changes. Over 1.2 million Type I and 60,005 Type 2 variants were obtained in the NCI-60 cell lines.
Since the NCI-60 panel has been used in the screening of thousands of compounds including FDA-approved and investigational drugs, it is a unique resource for testing the relationship of variants in genes to drug response. To demonstrate the usefulness of the WES data of the NCI-60 for novel hypothesis-driven research, an integrated pharmacogenomics investigation was conducted. The researchers used the Super Learner algorithm to predict the sensitivity of cells with Type 2 variants to 310 FDA approved or investigational anticancer drugs. They were able to study the correlations between key cancer-related variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and clinically relevant targeted agents.
The researchers’ findings establish that the comprehensive WES dataset will allow increased accuracy when using NCI-60 cell lines as experimental models and will expand the utility of other cell line panels for drug development. For example, when a genomic variant is discovered as a molecular target using other cell line resources, the WES data can be used to potentially identify screened compounds with selective activity for that target.
This study has generated a comprehensive list of cancer-related genetic variants that provides a valuable opportunity to identify additional mechanisms of drug resistance and potentially offers new ways to overcome acquired resistance and target genomic defects. To increase the utility of the dataset, the genomic variants are available to all researchers in different formats and from several websites including CellMiner (http://discover.nci.nih.gov/cellminer) and Ingenuity.Summary Posted: Mon, 07/01/2013
Abaan OD, Polley EC, Davis SR, Zhu YJ, Bilke S, Walker RL, Pineda M, Gindin Y, Jiang Y, Reinhold WC, Holbeck SL, Simon RM, Doroshow JH, Pommier Y, Meltzer PS. The exomes of the NCI-60 panel: a genomic resource for cancer biology and systems pharmacology. Cancer Research. July 15 2013 PubMed Link