Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.
Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.
化疗药物被用于治疗多种癌症，但个体之间的耐药性和毒性差异限制了治疗效果。多项研究表明，不同癌症类型的患者中，其祖源与治疗结果存在差异。我们使用传统的基于 SNP 的方法和新开发的基于基因的全基因组方法，研究了源自 83 名非裔美国人的淋巴母细胞系中化疗药物敏感性的遗传基础。由于在这个混合人群中存在群体结构，我们将局部祖源信息纳入我们的关联模型中。我们检测了超过 200 万个 SNP，分别鉴定出 325、176、240 和 190 个 SNP 与阿糖胞苷、5'-去氧氟尿苷（5'-DFUR）、卡铂和顺铂诱导的细胞毒性呈显著相关（p≤10(-4)）。重要的是，其中一些变体仅存在于非洲裔人群中。我们还表明，顺铂敏感性 SNP 富集了卡铂敏感性 SNP。使用基于基因的全基因组关联方法，我们分别鉴定出 26、11、20 和 41 个候选基因与阿糖胞苷、5'-DFUR、卡铂和顺铂诱导的细胞毒性呈显著相关（p≤10(-3)）。其中 14 个基因在来自尼日利亚伊巴丹的约鲁巴人中有其与各自化疗表型相关的证据（p<0.05），包括已知参与肿瘤发生的 TP53I11、COPS5 和 GAS8。尽管我们的结果需要进一步研究，但我们已经通过一种纳入局部祖源信息的方法，鉴定出与非裔美国人化疗药物敏感性相关的变体和基因。
