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.
Bibliographical noteFunding Information:
This study is supported by NIH/NIGMS Pharmacogenomics of Anticancer Agents grant U01GM61393 (NJC, MED), the University of Chicago Breast Cancer SPORE P50 CA125183 (RSH, NJC, MED), NIH/NIGMS grant K08GM089941 (RSH) and University of Chicago Cancer Center Support Grant P30 CA14599 (RSH, MED). We would like to thank the Pharmacogenomics of Anticancer Agents Cell Line Core for assistance in providing and maintaining these cell lines. In addition, we thank Marleen Welsh for phenotyping some of the ASW and CEU3 cell lines, and Wei Zhang for performing initial imputation analyses in the CHD.