p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
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DOI：
10.1097/01.fpc.0000204997.84182.69
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发表时间：
2006-05
影响因子：
2.6
通讯作者：
P. Wegman;Olle Sta˚l;M. Stenmark Askmalm;B. Nordenskjöld;L. Rutqvist;S. Wingren
中科院分区：
文献类型：
--
作者：
P. Wegman;Olle Sta˚l;M. Stenmark Askmalm;B. Nordenskjöld;L. Rutqvist;S. Wingren
背景乳腺癌患者的辅助治疗降低了复发和死亡的风险，尽管相当大比例的患者获得了疾病的耐药性和复发。因此，治疗反应的预测对于避免治疗抗性和无效方案的副作用是重要的。p53蛋白是细胞毒应激诱导生长停滞或凋亡的关键决定因素。方法在寻找癌症治疗的预测标志物时，我们研究了p53基因中常见的Arg 72/Pro72多态性，该多态性已被证明会影响凋亡潜力。使用PCR和RFLP，我们对220例乳腺癌患者进行了基因分型，这些患者被随机分为放疗组和化疗组，以及三苯氧胺组和非三苯氧胺组。结果雌激素受体阳性患者中，至少有一个Pro72等位基因的患者在随机分配到他莫昔芬组时，其无远处复发生存率高于非他莫昔芬组（P=0.0033），风险比也显著降低（HR=0.28，95%CI 0.12-0.65）。在Arg 72基因型纯合子患者中，他莫昔芬治疗组和非他莫昔芬治疗组的结局大致相同（P=0.65）。当计算出的风险比的基因型进行比较的相互作用测试的显着差异（P=0.0088）。结论p53基因第72密码子多态性可能是三苯氧胺疗效的预测因子，提示缺失Pro72等位基因的乳腺癌患者可能是其他治疗方案的候选者。
Background Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress. Methods In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen. Results Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088). Conclusion The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.