title: Genome-wide meta-analysis identifies variants associated with platinating agent susceptibility across populations.
abstract: Platinating agents are used in the treatment of many cancers, yet they can induce toxicities and resistance that limit their utility. Using previously published and additional world population panels of diverse ancestry totaling 608 lymphoblastoid cell lines (LCLs), we performed meta-analyses of over 3 million single-nucleotide polymorphisms (SNPs) for both carboplatin- and cisplatin-induced cytotoxicity. The most significant SNP in the carboplatin meta-analysis is located in an intron of NBAS (neuroblastoma amplified sequence; P=5.1 × 10(-7)). The most significant SNP in the cisplatin meta-analysis is upstream of KRT16P2 (P=5.8 × 10(-7)). We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Most of the variants that associate with platinum-induced cytotoxicity are polymorphic across multiple world populations; therefore, they could be tested in follow-up studies in diverse clinical populations. Seven genes previously implicated in platinating agent response, including BCL2 (B-cell CLL/lymphoma 2), GSTM1 (glutathione S-transferase mu 1), GSTT1, ERCC2 and ERCC6, were also implicated in our meta-analyses.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: E R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: A L
authors.initials: AL
authors.lastname: Stark
authors.forename: P H
authors.initials: PH
authors.lastname: O'Donnell
authors.forename: L K
authors.initials: LK
authors.lastname: Gorsic
authors.forename: R S
authors.initials: RS
authors.lastname: Huang
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D016190:Carboplatin / Q000009:adverse effects / Q000627:therapeutic use; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects* / Q000235:genetics*
chemical_list: C117339:NBAS protein, human; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D016190:Carboplatin; D002945:Cisplatin