title: Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  RESULTS
  Although treatment with 5'-deoxyfluorouridine and pemetrexed for up to 24 h resulted in low levels of apoptosis or interindividual variation in caspase-dependent cell death; paclitaxel, cisplatin, carboplatin, and cytarabine treatment for 24 h resulted in 9.4-fold, 9.1-fold, 7.0-fold, and 6.0-fold increases in apoptosis relative to control, respectively. There was a weak correlation between caspase activity and cytotoxicity (r(2)=0.03-0.29) demonstrating that cytotoxicity and apoptosis are two distinct phenotypes that may produce independent genetic associations. Estimated heritability (h(2)) for apoptosis was 0.57 and 0.29 for cytarabine (5 and 40 μmol/l, respectively), 0.22 for paclitaxel (12.5 nmol/l), and 0.34 for cisplatin (5 μmol/l). In the genome-wide association study using the HapMap CEU panel, we identified a significant enrichment of cisplatin-induced cytotoxicity SNPs within the significant cisplatin-induced apoptosis SNPs and an enrichment of expression quantitative trait loci (eQTL). Among these eQTLs, we identified several eQTLs with known function related to apoptosis and/or cytotoxicity.
  
  
  CONCLUSIONS
  Our study identifies apoptosis as a phenotype for pharmacogenomic studies in lymphoblastoid cell lines after treatment with paclitaxel, cisplatin, carboplatin, and cytarabine that may have utility for discovering biomarkers to predict response to certain chemotherapeutics.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wen
authors.forename: Lidija K
authors.initials: LK
authors.lastname: Gorsic
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Dana M
authors.initials: DM
authors.lastname: Ziliak
authors.forename: Rong Stephanie
authors.initials: RS
authors.lastname: Huang
authors.forename: Mary Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D016190:Carboplatin / Q000494:pharmacology; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D005467:Floxuridine / Q000494:pharmacology; D055106:Genome-Wide Association Study; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D000068437:Pemetrexed; D010597:Pharmacogenetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics; D014430:Twins, Monozygotic
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D005971:Glutamates; D005467:Floxuridine; D003561:Cytarabine; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; C025034:doxifluridine