Grupo de Oncologia Molecular-CI, Edifício Laboratórios, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, 4º piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Mol Biol Rep. 2013 Aug;40(8):4819-26. doi: 10.1007/s11033-013-2578-3. Epub 2013 May 5.
Renal cell carcinoma (RCC) is the most common cancer of the adult kidney and its incidence and mortality has increase in the last 20 years. The disruption of cellular death is one the mechanism involved in cancer development. This process is precise regulated by apoptotic and anti-apoptotic molecules. Survivin (BIRC5) is a member of the inhibitor of apoptosis protein family and has the ability to inhibit the activation of the pro-apoptotic caspase-9 (CASP9). Thus BIRC5 and CASP9 functional polymorphisms might modulate the apoptosis and consequently RCC development. Our purpose was to investigate the potential role of BIRC5-31G/C and CASP9+83C/T functional polymorphisms in the risk for the development of RCC and metastatic disease. We studied the BIRC5-31G/C and CASP9+83C/T functional polymorphisms by PCR-RFLP and allelic discrimination using the 7300 real-time polymerase chain reaction system, respectively, in 178 RCC patients and in 305 healthy individuals. Regarding the BIRC5-31G/C polymorphism, there is a trend to an overrepresentation of CC genotype in RCC group compared with normal controls (aOR, 1.94; P=0.053). We observed, after gender stratification and age-adjustment, that BIRC5-31CC and CASP9+83CT/TT genotypes were associated with an increased risk for RCC development in the female group of our southern European study population (aOR=3.85; P=0.019; aOR=2.98; P=0.028; respectively). Concerning the waiting time for onset of metastatic disease, we observed that BIRC5-31CC homozygous developed metastasis 8 years earlier than the G carriers using a Cox proportional hazard model with gender as covariate (HR=4.9, P=0.038, P bootstrap=0.009). The Cox regression proportional hazard model was validated using bootstrap statistic with 1,000 samples of the same number of patients as the original dataset. Our results suggest that individual differences influence the susceptibility to RCC and tumor behavior. This genetic profile may help to define higher risk groups that would benefit from individualized chemoprevention strategies and therapies.
肾细胞癌 (RCC) 是成人肾脏最常见的癌症，其发病率和死亡率在过去 20 年中有所增加。细胞死亡的中断是癌症发展过程中涉及的机制之一。这个过程由凋亡和抗凋亡分子精确调节。Survivin (BIRC5) 是凋亡抑制蛋白家族的一员，具有抑制促凋亡 caspase-9 (CASP9) 激活的能力。因此，BIRC5 和 CASP9 功能性多态性可能调节细胞凋亡，进而影响 RCC 的发生。我们的目的是研究 BIRC5-31G/C 和 CASP9+83C/T 功能性多态性在 RCC 发展和转移疾病风险中的潜在作用。我们通过 PCR-RFLP 研究了 BIRC5-31G/C 多态性，通过 7300 实时聚合酶链反应系统研究了 CASP9+83C/T 多态性，分别在 178 名 RCC 患者和 305 名健康个体中进行。关于 BIRC5-31G/C 多态性，与正常对照组相比，RCC 组中 CC 基因型的表达有上升趋势(aOR，1.94；P=0.053)。我们观察到，在进行性别分层和年龄调整后，BIRC5-31CC 和 CASP9+83CT/TT 基因型与我们南欧研究人群中女性 RCC 发病风险增加相关(aOR=3.85；P=0.019；aOR=2.98；P=0.028；分别)。关于转移性疾病发病等待时间，我们观察到 Cox 比例风险模型中 BIRC5-31CC 纯合子比 G 携带者更早出现转移(HR=4.9，P=0.038，P bootstrap=0.009)，该模型将性别作为协变量。使用相同数量的患者的原始数据集的 1000 个样本的 bootstrap 统计数据验证了 Cox 回归比例风险模型。我们的结果表明，个体差异影响 RCC 的易感性和肿瘤行为。这种遗传特征可能有助于确定更高风险的群体，这些群体将受益于个体化的化学预防策略和治疗。
