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首页> 外文期刊>Cancer science. >Genome‐wide association study of chemotherapeutic agent‐induced severe neutropenia/leucopenia for patients in Biobank Japan
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Genome‐wide association study of chemotherapeutic agent‐induced severe neutropenia/leucopenia for patients in Biobank Japan

机译：日本Biobank中化学治疗剂引起的严重中性粒细胞减少/白细胞减少症的全基因组关联研究

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AbstractChemotherapeutic 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.
机译：摘要众所周知，化学治疗剂的治疗范围很窄，通常会危及生命。因此，通过药物基因组学方法鉴定对某些化学疗法有严重毒性高风险的患者在临床上很重要。在这项研究中，我们对13122名接受不同化疗方案的癌症患者进行了全基因组关联研究（GWAS），包括环磷酰胺和铂类药物（顺铂和卡铂），蒽环类药物（阿霉素和表柔比星）以及基于抗代谢物的治疗（5-氟尿嘧啶和吉西他滨），抗微管药（紫杉醇和多西他赛）和拓扑异构酶抑制剂（喜树碱和依托泊苷），以及与紫杉醇和卡铂联合治疗，以鉴定与遗传风险相关的基因变异日本人群中有严重的中性粒细胞减少/白细胞减少症。此外，我们使用加权遗传风险评分系统评估了从GWAS鉴定出的暗示性遗传变异的累积效应，以便预测携带多个风险等位基因的个体的风险水平。尽管我们无法通过GWAS识别出超过全基因组显着性水平（P <5.0×10 −8 ）的遗传变异，可能是由于统计能力不足和复杂的临床特征所致，但我们还是能够入围一些暗示性的相关基因座。目前的研究还处于初期阶段，但确实突出了与回顾性药物基因组学研究相关的复杂性和问题性问题。但是，我们希望通过本地和国际合作对这些遗传变异的验证可以改善癌症患者的临床结局。

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