Department of Biochemistry, University of Allahabad, Prayagraj, Uttar Pradesh, India.
Department of Radiation Oncology, Kamala Nehru Memorial Hospital, Uttar Pradesh, India.
J Cancer Res Ther. 2024 Jan 1;20(1):289-296. doi: 10.4103/jcrt.jcrt_1897_22. Epub 2023 Jun 26.
Majority of the gallbladder cancer (GBC) cases are diagnosed at an advanced stage where chemotherapy alone (or in combination with other treatment methods) is mainly opted as therapeutic approach. However, success or failure of this approach largely depends on the interindividual genetic differences. Careful consideration on the genetic association could assist in the evaluation of patient's treatment response and survival rate. Hence, the present study aims to investigate the survival of patients with GBC and their treatment response to gemcitabine and cisplatin/carboplatin-based chemotherapy in association with Glutathione S-transferase (GSTs) gene polymorphism.
A total of 216 histologically confirmed cases of gallbladder cancer were recruited. A total of 180 patients were treated with gemcitabine and cisplatin/carboplatin-based chemotherapy. GSTM1, GSTT1, and GSTP1 genotypes were determined by multiplex PCR and by PCR restriction fragment length polymorphism (PCR-RFLP), respectively. The influence of genetic polymorphism on overall survival was analyzed by Kaplan-Meier method, survival rate difference was analyzed by log-rank test, and hazard ratio for mortality outcomes was estimated using Cox regression method.
GBC patients having genotype GSTP1 (AG + GG) showed poor 3-year survival rate of 0.8% compared to 10.9% of GSTP1 (AA) genotype (χ2 = 6.456, P = 0.011). The multivariate Cox regression results showed that the death risk was significantly higher in GSTP1 (AG + GG) genotype (HR = 3.858, P = 0.050). We found no association of GSTM1 and GSTT1 gene polymorphism with the survival; however, the combined genotypes of GSM1/GSTP1, GSTT1/GSTP1, and GSTM1/GSTT1/GSTP1 were associated with survival (P = 0.053, 0.006, and 0.058, respectively). Increased death hazard was noted by the genotype combinations of GSTM1+/GSTP1AG + GG (HR = 3.484, P = 0.024), GSTM1-/GSTP1AG + GG (HR = 2.721, P = 0.014), GSTT1+/GSTP1AG + GG (HR = 20.690, P = 0.001), and GSTT1-/GSTP1AA (HR = 26.111, P < 0.0001). Our findings indicate that chemotherapy treatment response of GSTP1 (AG + GG) has 1.62-fold increased risk for progression compared to GSTP1 (AA) genotype (p = 0.018); however, none of the genotypes showed association with overall survival and death risk after chemotherapeutic treatment.
We found that the presence of GSTP1 (AG + GG) genotype showed survival disadvantage and poor treatment outcomes in response to gemcitabine and cisplatin/carboplatin-based chemotherapy. This could serve as biomarker, and future research in pharmacogenomics will definitely pave the way for the development of better treatment approach for GBC.
大多数胆囊癌（GBC）病例在晚期被诊断出来，此时主要选择化疗（或联合其他治疗方法）作为治疗方法。然而，这种方法的成败在很大程度上取决于个体的遗传差异。仔细考虑遗传相关性可以帮助评估患者的治疗反应和生存率。因此，本研究旨在探讨 GST 基因多态性与吉西他滨和顺铂/卡铂为基础的化疗治疗 GBC 患者的生存和治疗反应的关系。
共纳入 216 例经组织学证实的胆囊癌患者。180 例患者接受吉西他滨和顺铂/卡铂为基础的化疗。采用多重 PCR 和 PCR 限制性片段长度多态性（PCR-RFLP）分别检测 GSTM1、GSTT1 和 GSTP1 基因型。采用 Kaplan-Meier 法分析遗传多态性对总生存率的影响，采用对数秩检验分析生存率差异，采用 Cox 回归法估计死亡率的危险比。
GBC 患者 GSTP1（AG+GG）基因型的 3 年生存率为 0.8%，明显低于 GSTP1（AA）基因型的 10.9%（χ2=6.456，P=0.011）。多变量 Cox 回归结果显示，GSTP1（AG+GG）基因型的死亡风险明显更高（HR=3.858，P=0.050）。我们没有发现 GSTM1 和 GSTT1 基因多态性与生存有关；然而，GSM1/GSTP1、GSTT1/GSTP1 和 GSTM1/GSTT1/GSTP1 的联合基因型与生存有关（P=0.053、0.006 和 0.058）。GSTM1+/GSTP1AG+GG（HR=3.484，P=0.024）、GSTM1-/GSTP1AG+GG（HR=2.721，P=0.014）、GSTT1+/GSTP1AG+GG（HR=20.690，P=0.001）和 GSTT1-/GSTP1AA（HR=26.111，P<0.0001）基因型组合的死亡风险增加。我们的研究结果表明，与 GSTP1（AA）基因型相比，GSTP1（AG+GG）基因型的化疗治疗反应进展风险增加了 1.62 倍（p=0.018）；然而，在化疗治疗后，没有任何基因型与总生存率和死亡风险有关。
我们发现 GSTP1（AG+GG）基因型的存在表明在吉西他滨和顺铂/卡铂为基础的化疗治疗中生存不利和治疗效果不佳。这可以作为一个生物标志物，未来的药物基因组学研究肯定会为 GBC 的治疗方法的发展开辟道路。
