Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell linesReportar como inadecuado




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BMC Genomics

, 15:93

First Online: 01 February 2014Received: 07 June 2013Accepted: 10 January 2014DOI: 10.1186-1471-2164-15-93

Cite this article as: Li, L., Fridley, B.L., Kalari, K. et al. BMC Genomics 2014 15: 93. doi:10.1186-1471-2164-15-93

Abstract

BackgroundTwo cytidine analogues, gemcitabine and cytosine arabinoside AraC, are widely used in the treatment of a variety of cancers with a large individual variation in response. To identify potential genetic biomarkers associated with response to these two drugs, we used a human lymphoblastoid cell line LCL model system with extensive genomic data, including 1.3 million SNPs and 54,000 basal expression probesets to perform genome-wide association studies GWAS with gemcitabine and AraC IC50 values.

ResultsWe identified 11 and 27 SNP loci significantly associated with gemcitabine and AraC IC50 values, respectively. Eleven candidate genes were functionally validated using siRNA knockdown approach in multiple cancer cell lines. We also characterized the potential mechanisms of genes by determining their influence on the activity of 10 cancer-related signaling pathways using reporter gene assays. Most SNPs regulated gene expression in a trans manner, except 7 SNPs in the PIGB gene that were significantly associated with both the expression of PIGB and gemcitabine cytotoxicity.

ConclusionThese results suggest that genetic variation might contribute to drug response via either cis- or trans- regulation of gene expression. GWAS analysis followed by functional pharmacogenomics studies might help identify novel biomarkers contributing to variation in response to these two drugs and enhance our understanding of underlying mechanisms of drug action.

KeywordsCytidine analogues Gemcitabine Cytosine arabinoside Lymphoblastoid cell lines Expression array Genome-wide SNPs Genome-wide association study Functional genomics Translational research AbbreviationsAraCCytosine arabinoside

LCLLymphoblastoid cell line

RRM1Ribonucleotide reductase

CDACytidine deaminase

CACaucasian-American

AAAfrican-American

HCAAfrican-American

EMSAElectrophoresis mobility shift assays

QRT-PCRQuantitative reverse transcription-PCR

QCQuality control

HWEHardy-Weinberg equilibrium

AMLAcute myelogenous leukemia

TFTranscription factors

GWASGenome-wide association studies

LDLinkage disequilibrium.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-15-93 contains supplementary material, which is available to authorized users.

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Autor: Liang Li - Brooke L Fridley - Krishna Kalari - Nifang Niu - Gregory Jenkins - Anthony Batzler - Ryan P Abo - Daniel Scha

Fuente: https://link.springer.com/







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