oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data.

Cell line drug screening datasets can be utilized for a range of different drug discovery applications from drug biomarker discovery to building translational models of drug response. Previously, we described three separate methodologies to (1) correct for general levels of drug sensitivity to enable drug-specific biomarker discovery, (2) predict clinical drug response in patients and (3) associate these predictions with clinical features to perform in vivo drug biomarker discovery. Here, we unite and update these methodologies into one R package (oncoPredict) to facilitate the development and adoption of these tools.

Discovering drugs to overcome chemoresistance in ovarian cancers based on the cancer genome atlas tumor transcriptome profile.

Ovarian cancer accounts for the highest mortality among gynecologic cancers, mainly due to intrinsic or acquired chemoresistance. While mechanistic-based methods have been used to identify compounds that can overcome chemoresistance, an effective comprehensive drug screening has yet to be developed. We applied a transcriptome based drug sensitivity prediction method, to the Cancer Genome Atlas (TCGA) ovarian cancer dataset to impute patient tumor response to over 100 different drugs.

Institutional Profile: Pharmacogenomic research in R Stephanie Huang Laboratory.

The Huang Lab was established in 2009 at the University of Chicago and has since been active in conducting pharmacogenomic research. Our laboratory's main research focus is translational pharmacogenomics with a particular interest in the pharmacogenomics of anticancer agents. By systematically evaluating the human genome and its relationships to drug response and toxicity, our goal is to develop clinically useful models that predict risk for adverse drug reactions and nonresponse prior to administration of chemotherapy.

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity.

Background: Using genome-wide genetic, gene expression, and microRNA expression (miRNA) data, we developed an integrative approach to investigate the genetic and epigenetic basis of chemotherapeutic sensitivity.

Results: Through a sequential multi-stage framework, we identified genes and miRNAs whose expression correlated with platinum sensitivity, mapped these to genomic loci as quantitative trait loci (QTLs), and evaluated the associations between these QTLs and platinum sensitivity. A permutation analysis showed that top findings from our approach have a much lower false discovery rate compared to those from a traditional GWAS of drug sensitivity.

Apolipoprotein A5 gene variants and the risk of coronary heart disease: a case‑control study and meta‑analysis.

Previous studies have shown that apolipoprotein A5 (APOA5) gene variants are genetic determinants of the concentration of triglycerides, which are a known risk factor for coronary heart disease (CHD). Using the standardized coronary angiography method, 290 CHD patients and 198 non‑CHD controls were recruited from Ningbo Lihuili Hospital. In addition, 331 unrelated healthy volunteers were recruited as healthy controls from Ningbo Ximen Community residents.

Genetic variation that predicts platinum sensitivity reveals the role of miR-193b* in chemotherapeutic susceptibility.

Platinum agents are the backbone of cancer chemotherapy. Recently, we identified and replicated the role of a single nucleotide polymorphism (SNP, rs1649942) in predicting platinum sensitivity both in vitro and in vivo. Using the CEU samples from the International HapMap Project, we found the same SNP to be a master regulator of multiple gene expression phenotypes, prompting us to investigate whether rs1649942-mediated regulation of miRNAs may in part contribute to variation in platinum sensitivity.

Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

Aim: To determine whether cellular apoptosis is a suitable phenotypic trait for pharmacogenomics studies by evaluating caspase 3/7-mediated activity in lymphoblastoid cell lines after treatment with six chemotherapeutic agents: 5'-deoxyfluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin, and cisplatin.

Materials And Methods: Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase 3/7 activity in lymphoblastoid cell lines. Genome-wide association studies were performed with over 2 million single nucleotide polymorphisms (SNPs) and cisplatin-induced apoptosis in HapMap CEU cell lines (n=77).

Comprehensive evaluation of the contribution of X chromosome genes to platinum sensitivity.

Using a genome-wide gene expression data set generated from Affymetrix GeneChip Human Exon 1.0ST array, we comprehensively surveyed the role of 322 X chromosome gene expression traits on cellular sensitivity to cisplatin and carboplatin. We identified 31 and 17 X chromosome genes whose expression levels are significantly correlated (after multiple testing correction) with sensitivity to carboplatin and cisplatin, respectively, in the combined HapMap CEU (Utah residents with ancestry from northern and western Europe) and YRI (Yoruba in Ibahan, Nigeria) populations (false discovery rate, FDR < 0.

PACdb: a database for cell-based pharmacogenomics.

We have developed Pharmacogenomics And Cell database (PACdb), a results database that makes available relationships between single nucleotide polymorphisms, gene expression, and cellular sensitivity to various drugs in cell-based models to help determine genetic variants associated with drug response. The current version also supports summary analysis on differentially expressed genes between the HapMap samples of European and African ancestry, as well as queries for summary information of correlations between gene expression and pharmacological phenotypes. At present, data generated on the following anticancer agents are included: carboplatin, cisplatin, etoposide, daunorubicin, and cytarabine (Ara-C).

Identification of genetic variants and gene expression relationships associated with pharmacogenes in humans.

Objectives: The very important pharmacogenes (VIPs) were selected by Pharmacogenetic Research Network (National Institutes of Health-PGRN) owing to their significant effects on drug treatment both at the pharmacokinetic and pharmacodynamic levels. Our objective was to identify single nucleotide polymorphisms (SNPs) that potentially affected the expression of these genes or potential SNP-gene interactions involved to improve our understanding of genetic effects on drug therapy.

Basic Methods: Gene expression was evaluated in 176 International HapMap lymphoblastoid cell lines derived from CEU (CEPH, Utah residents with ancestry from northern and western Europe; n=87) and YRI (Yoruba in Ibadan, Nigeria; n=89) using Affymetrix GeneChip Human Exon 1.

Mapping genes that contribute to daunorubicin-induced cytotoxicity.

Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity.

Effect of population and gender on chemotherapeutic agent-induced cytotoxicity.

Large interindividual variance is observed in both response and toxicity associated with chemotherapy. Our goal is to identify factors that contribute to chemotherapy-induced toxicity. To this end, we used EBV-transformed B-lymphoblastoid HapMap cell lines derived from 30 Yoruban trios (African descent) and 30 Centre d' Etude du Polymorphisme Humain (CEPH) trios (European descent) to evaluate population- and gender-specific differences in cytotoxicity of carboplatin, cisplatin, daunorubicin, and etoposide using a high-throughput, short-term cytotoxicity assay.