Zhang Xue, Yin Jia-Fu, Zhang Jiao, Kong Shu-Jia, Zhang Hong-Yin, Chen Xue-Mei
Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China.
Department of Pathology, College of Basic Medicine, Dali University, Dali, 671000, People's Republic of China.
Cancer Chemother Pharmacol. 2017 Jul;80(1):135-149. doi: 10.1007/s00280-017-3344-3. Epub 2017 Jun 5.
Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A16 and 28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A16 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A16 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A16 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A16 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A16 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD = 0.11, P < 0.001). Specifically, the heterozygous variant of UGT1A16 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD = 0.09, P < 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD = 0.18, P < 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A16 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD = 0.08, P = 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD = 0.15, P = 0.001). In conclusion, in this meta-analysis, the UGT1A16 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.
伊立替康（IRI）化疗毒性可能很严重，可能导致治疗延迟、发病，在某些罕见情况下甚至会导致死亡。中性粒细胞减少是伊立替康的一种危及生命的副作用，尿苷二磷酸葡萄糖醛酸转移酶（UGTs）基因多态性可以预测癌症患者的副作用，进而通过预防性治疗或降低剂量来降低IRI诱导的毒性。UGT1A16和28均被可靠地证明是IRI诱导的中性粒细胞减少的危险因素，对这两种多态性进行检测可能对亚洲癌症患者特别有用。然而，一些研究人员报告称UGT1A16可以预测亚洲人群中IRI诱导的毒性，争议性结论仍然存在。因此，仍需要探索UGT1A16多态性与癌症患者中IRI诱导的严重毒性之间的关联。因此，本研究旨在大规模调查癌症患者中UGT1A16多态性与IRI相关的严重中性粒细胞减少之间的关联。根据纳入标准，共纳入了12项研究，其中包括746例野生基因型（G/G）病例和394例变异基因型（G/A和A/A）病例。然后我们评估了方法学质量；使用比值比（OR）、风险差（RD）和95%置信区间（95%CI）来评估关联强度。总体而言，发现UGT1A16多态性的癌症患者发生严重中性粒细胞减少的风险增加。UGT1A16隐性模型（GA + AA vs. GG）的患者显示风险增加（OR 2.03，95%CI 1.54 - 2.68；RD = 0.11，P < 0.001）。具体而言，UGT1A16的杂合变异显示风险增加（OR 1.83，95%CI 1.36 - 2.46；RD = 0.09，P < 0.001），纯合突变也显示严重中性粒细胞减少的高风险（OR 2.95，95%CI 1.83 - 4.75；RD = 0.18，P < 0.001）。亚组荟萃分析显示，对于同时携带杂合和纯合变异的患者，癌症类型、低剂量IRI和治疗持续时间也呈现出严重中性粒细胞减少风险的相应增加。至于国家，在中国和日本，UGT1A16变异基因型的严重中性粒细胞减少在统计学上有所增加（中国：GA + AA vs. GG，OR 1.83，95%CI 1.28 - 2.59；RD = 0.08，P = 0.001；日本：GA + AA vs. GG，OR 2.39，95%CI 1.45 - 3.92；RD = 0.15，P = 0.001）。总之，在这项荟萃分析中，UGT1A16多态性与癌症患者中IRI诱导的中性粒细胞减少风险增加相关，严重中性粒细胞减少发生率的增加可能与不同地区、癌症类型、低剂量IRI和治疗持续时间相关。
