Liu Dan, Li Jian, Gao Jing, Li Yanyan, Yang Rui, Shen Lin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China.
BMC Cancer. 2017 Jun 20;17(1):437. doi: 10.1186/s12885-017-3406-2.
To evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).
The genotypes of UGT1A (UGT1A16, UGT1A127, UGT1A128, UGT1A72, UGT1A73, UGT1A74 and UGT1A922) and DPYD (DPYD5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.
In the cohort studied here, the incidence of UGT1A16, UGT1A128, UGT1A72, UGT1A73, UGT1A922, DPYD5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A127 and DPYD2A had low frequencies and UGT1A74 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A128 heterozygotes (OR = 2.263, 95%CI 1.395-3.670), UGT1A128 homozygotes (OR = 5.910, 95%CI 1.138-30.672) and UGT1A16 homozygotes (OR = 4.737, 95%CI 1.946-11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136-4.041). Neither DPYD5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A128 and DPYD5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD5 was found to associate with better progression-free survival (P = 0.015). UGT1A127 contributed to worse overall survival (P < 0.001).
Results still showed UGT1A16 and UGT1A128 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A16 and UGT1A128, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.
评估一种新的UGT1A和DPYD基因多态性检测板，以更好地预测中国转移性结直肠癌（mCRC）患者中伊立替康引起的毒性反应及临床反应。
采用直接测序法检测661例接受含伊立替康化疗的mCRC患者的UGT1A（UGT1A16、UGT1A127、UGT1A128、UGT1A72、UGT1A73、UGT1A74和UGT1A922）和DPYD（DPYD5、DPYD c.1896 T>C和DPYD*2A）基因分型。评估UGT1A和DPYD基因多态性对严重伊立替康引起的毒性反应和临床结局的影响。
在本研究队列中，UGT1A16、UGT1A128、UGT1A72、UGT1A73、UGT1A922、DPYD5和DPYD c.1896 T>C变异的发生率分别为34.8%、24.2%、34.3%、39.4%、81.8%、48.4%和20.4%。UGT1A127和DPYD2A频率较低，未发现UGT1A74。共有59例患者（8.9%）发生严重腹泻，136例患者（20.6%）发生严重中性粒细胞减少。UGT1A128杂合子（OR=2.263，95%CI 1.395-3.670）、UGT1A128纯合子（OR=5.910，95%CI 1.138-30.672）和UGT1A16纯合子（OR=4.737，95%CI 1.946-11.533）是严重中性粒细胞减少的独立危险因素。未发现UGT1A基因多态性与严重腹泻有关。DPYD5被确定为严重腹泻的独立危险因素（OR=2.143，95%CI 1.136-4.041）。未发现DPYD5和DPYD c.1896 T>C与严重中性粒细胞减少有关。在一线含伊立替康治疗中，UGT1A128和DPYD5导致更高的缓解率（分别为P=0.043和P=0.019），而DPYD5与更好的无进展生存期有关（P=0.015）。UGT1A127导致更差的总生存期（P<0.001）。
结果仍显示UGT1A16和UGT1A128与伊立替康引起的毒性反应和临床反应部分相关。除UGT1A16和UGT1A128外，检测更多的UGT1A基因位点无助于提高基于伊立替康的毒性和疗效的预测价值。检测DPYD*5有助于预测严重腹泻。
