Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine

Abstract

For the Focus Section on PharmacogeneticsChemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genomebased technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the genetic and drug response data of the NCI60 cell lines to discover potential candidate genetic variants associated with variable response to chemotherapy. As an example we have applied this strategy to discover single genetic markers and haplotypes from candidate genes previously implicated in the pharmacobiology of gemcitabine. Single-marker association analyses have implicated the association of four SNPs within the gene loci of CDC5L, EPC2, POLS, and PARP1. We have also investigated the combined effect of SNPs using haplotype-based analysis. Accordingly, we have shown modest association of haplotypes in six genes, whereas the most significant associations included a haplotype of the POLS gene. The hypothesis-generating tool presented in this study can be applied to drugs profiled in the NCI60 cell line screen and provides an effective means for the identification of genes associated with drug response. The results obtained using this novel methodology can be used to better design the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy. Hum Mutat 29(4), [461][462][463][464][465][466][467] 2008.

Pharmacogenomic Discovery Using Cell-Based Models

“…Studies using these cells have successfully identified polymorphisms in candidate genes associated with drug response in vitro (Le Morvan et al, 2006;Jarjanazi et al, 2008;Puyo et al, 2008;Sasaki et al, 2008). Methylation of certain promoter CpG islands predicts toxicity to antimetabolites and alkylating agents in the NCI-60 lines (Shen et al, 2007;Sasaki et al, 2008).…”

Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

“…2). The smallest antimode, observed at -6.875, was used as the cutoff value [26] between Resistant and Sensitive groups, as displayed by the vertical red line. After the above filtering steps, we produced a consolidated file containing the variant data and associated drug response values.…”

Molecular Biology and Therapeutics in Musculoskeletal Oncology*

“…When this technique was used on three Ewing sarcoma cell lines, IGF-1, and its receptor, a series of kinases and fibroblast growth-factor receptor 4 were identified as critical for cell growth. Similar experiments can be performed in combination with cytotoxic chemotherapy to identify maximal synergies and genes related to chemoresistance 41 . Validation in primary tumor specimens, data mining, identification of biomarkers that can be used to tailor therapy to the individual patient and tumor and to monitor the response to treatment, and, ultimately, clinical trials are all part of the process.…”

“…It was emphasized that public access to primary-expression profile data is critical as it enables external validation. Future directions may include massive parallel sequencing with ChIP (chromatin immunoprecipitation)-sequencing to survey transcriptionfactor binding across the genome, expression profiling direct from cDNA, and microRNA profiling 41 . Costs are high for equipment and data processing, analysis is complex, and standards for tissue banking need to be developed so as to not introduce artifacts into the system.…”