以多基因分析預測臺灣肺癌病人使用cisplatin或carboplatin 引起腎毒性之研究

Polygenic Analytic Approaches in Predicting Cisplatin or Carboplatin-induced Nephrotoxicity in Lung Cancer Patients in Taiwan

許育嘉(Yu-Chia Hsu)

指導教授 ： 劉興璟

共同指導教授 ： 陳香吟

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

鉑類藥物是目前使用最廣泛的化療藥品，常用於許多固態性腫瘤。然而，此類藥物最常引起的副作用-腎毒性也限制了其用途。即使給予適當輸注，仍約有三分之一病人會發生腎毒性。鉑類藥物引起腎毒性的機轉目前尚未有定論，但目前認為和許多途徑有關係，包括通道蛋白有關的細胞攝入或汲出、腎毒性物質代謝能力、基因修復能力及細胞凋亡。
本研究一共收入125位使用cisplatin或是carboplatin之肺癌病人，擬探討台灣族群16種基因共21個單一核苷酸基因多型性(ERCC1 C118T、ERCC4 T2505C,、XPD Arg156Arg、XPA G23A、OGG1 Ser326Cys,、APEX Asp148Glu、 NAT2 C481T、NAT2 G590A、NAT2G857A、MATE1 g-66T>C、MATE1G>A、OCT2 G808T、ABCB1 C3435T、ABCC2-24C>T、ERCC1 C8092A、XPG D1104H、GSTP1 A313G、TP53 G215C、NQO1 C609T、UGT1A7 T387G及UGT1A7 T622C)與鉑類藥物引起腎毒性之關聯性，並建立多基因預測模型，尋找腎毒性易感族群。
本研究顯示，總共有28名病患(22.2%)於接受鉑類化療期間曾發生腎毒性，並發現MATE1G>A、OCT2 G808T、NQO1 C609T、OGG1 C8069G和鉑類引起腎毒有關係(ORad=4.105, p=0.043、ORad=3.415, p=0.029、ORad=2.624, p=0.066 and ORad= 0.243, p=0.043)。此外，本研究也發現ERCC1 C118T、XPG 1104C 和 XPD G156T和carboplatin引起腎毒性有關(分別為OR=15.5, p=0.04、OR=6.79,p=0.038 and ORad=0.095, p=0.025,)。因此，依照與鉑類藥物相關的基因型，本研究分別建立cisplatin及carboplatin的多基因腎毒性預測模型。由ROC curve(Receiver Operating Characteristic curve)之AUC(area under curve)得知 ，cisplatin/carboplatin模型具良好預測能力(AUC=0.819及0.914)。根據此模型結果，進一步將病人分成高低腎毒性風險，結果顯示，於cisplatin或是carboplatin之使用者，高風險族群較低風險易發生腎毒性(HR= 4.621, p=0.006 and HR=13.891,p=0.016, respectively)，顯示多基因模型能幫助給鉑類化療藥前預測腎毒性高風險族群。

關鍵字

基因多型性 ； 腎毒性 ； 順鉑 ； 卡鉑 ； 肺癌

並列摘要

Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. However, severe nephrotoxicity limits its usage. Nephrotoxicity has been reported in 30% of patients treated with cisplatin along with the hydration. The precise mechanisms for platinum-induced nephrotoxicity is inconclusive and have been recognized to be associated with multiple complex pathway, which include alterations in drug influx or efflux, detoxification through glutathione conjugation, DNA repair capacity and other cellular pathways.
To investigate the association between genetic variations in candidate gene and platinum-induced nephrotoxicity in lung cancer patients in Taiwan, we collected blood samples of 125 lung cancer patients in Taipei Medical University-Wan Fang Hospital. 21 Polymorphisms within genes of ABCB1, MATE1, ABCC2, OCT2, XPD, XPA, OGG1, APEX, XPG, TP53, ERCC1, ERCC4, NAT2, NQO1 , UGT1A7 and GSTP1 were genotyped by polymerase chain reaction-based techniques.
Our finding suggested that 28 patients (22.4%) had occurred renal toxicity during platinum-based chemotherapy. The MATE1G>A, OCT2 G808T, NQO1 C609T, OGG1 C8069G were associated with platinum-induced nehprotoxicity (ORad=4.105, p=0.043、ORad=3.415, p=0.029、ORad=2.624, p=0.066 and ORad= 0.243, p=0.043, respectively). Also, we found that ERCC1 C118T、XPG G1104C and XPD G156T were associated with carboplatin-induced nephrotoxicity especially (OR=15.5, p=0.04、OR=6.79,p=0.038 and ORad=0.095, p=0.025, respectively). A polygenic model was created to predict cisplatin/carboplatin induced nephrotoxicity individually. Based on receiver operating characteristic curve (ROC curve) , each model has a good performance to predict nephrotoxicity (the AUC=0.819 and 0.904 , for cisplatin and carboplatin respectively). We classified patients into high/low risk group according to the polygenic model , both the high risk group is significantly associated with nephrotoxicity compared with low risk group in cisplatin/carboplatin subgroup (HR= 4.621, p=0.006 and HR=13.891,p=0.016, respectively).
In conclusion, we identified genetic risk factors for cisplatin/carboplatin induced nephrotoxicity , respectively. It suggested that the polygenic model can help to predict high risk for platinum-iduced nephrotoxicity in lung cancer before chemotherapy.

並列關鍵字

genetic polymorphism ； nephrotoxicity ； cisplatin ； carboplatin ； lung cancer

參考文獻

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