Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Yokohama, Japan.
Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.
Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide- and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 × 10(-8) ) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients.
化疗药物众所周知具有狭窄的治疗范围，往往导致危及生命的毒性。因此，通过药物基因组学方法识别某些化疗药物发生严重毒性的高危患者具有重要的临床意义。在这项研究中，我们对 13122 名接受不同化疗方案（包括环磷酰胺和铂类（顺铂和卡铂）、蒽环类（多柔比星和表柔比星）、抗代谢物类（5-氟尿嘧啶和吉西他滨）、抗微管药物（紫杉醇和多西紫杉醇）和拓扑异构酶抑制剂（喜树碱和依托泊苷）以及紫杉醇和卡铂联合治疗）的癌症患者进行了多次全基因组关联研究（GWAS），以鉴定与日本人群严重中性粒细胞减少/白细胞减少风险相关的遗传变异。此外，我们使用加权遗传风险评分系统来评估从 GWAS 中确定的提示遗传变异的累积效应，以预测携带多个风险等位基因的个体的风险水平。尽管我们未能通过 GWAS 确定超过全基因组显著水平（P<5.0×10(-8)）的遗传变异，可能是由于统计效力不足和复杂的临床特征，但我们能够确定一些提示相关的基因座。目前的研究处于相对初步阶段，但确实突出了回顾性药物基因组学研究的复杂性和问题。然而，我们希望通过本地和国际合作验证这些遗传变异，能够改善癌症患者的临床结局。
