基质金属蛋白酶-2、8 基因启动子中单核苷酸多态性与印度北部膀胱癌风险的关联。

Association of single nucleotide polymorphisms in promoter of matrix metalloproteinase-2, 8 genes with bladder cancer risk in Northern India.

机构信息

Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

出版信息

Urol Oncol. 2013 Feb;31(2):247-54. doi: 10.1016/j.urolonc.2011.01.001. Epub 2011 Jul 23.

DOI:10.1016/j.urolonc.2011.01.001

PMID:21784671

Abstract

OBJECTIVE

Matrix metalloproteinases (MMPs) are expressed in melanocytes and their overexpression has been linked to tumor development, progression, and metastasis. At the genetic level, following functional promoter polymorphisms are known to modify the gene transcription: -1306 C > T, -735 C > T in MMP2, and 799 C > T in MMP8 gene. Hence we hypothesize that functional polymorphisms in the 2 MMP SNPs in promoter region may modulate the risk for bladder cancer (BC) progression in North Indian population.

MATERIALS AND METHODS

Genotyping for these polymorphisms were done in a group of 200 BC and 200 age matched, similar ethnicity unrelated healthy controls using PCR-based methods. Two-sided χ(2), Cox-regression was utilized to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known BC confounders such as age and gender. Survival analysis was done using the Kaplan-Meier method and differences in survival were assessed using the log rank test.

RESULTS

Individuals with MMP2 (-1306) TT genotype as well as T allele were at higher risk of BC (P, 0.042; OR, 2.85; P, 0.001; OR, 1.76). This effect was even more apparent in case of CT+TT (P < 0.001; OR, 2.61). In MMP2 (735), CT+TT demonstrated significant risk (P, 0.034; OR, 1.66). In MMP8 (799), reduced risk was observed with TT genotype (P, 0.006; OR, 0.27). Haplotype analysis showed that individuals with haplotype 735C-1306T and 735T-1306C were at 1.9- and 1.5-fold higher risk. MMP2 -1306CC in combination with MMP8 799CT genotype showed protective effect. The genotype CT and CT+TT of MMP2 1306C > T were associated with high risk of recurrence in BCG treated patients (HR, 4.32; P, 0.006 and HR, 2.06; P, 0.047) thus showing reduced recurrence free survival (CT+TT/CC = 34/45 months; log rank P, 0.039).

CONCLUSION

Our data suggested that variant allele of MMP2 1306C > T was associated with high risk of tumor recurrence and reduced recurrence free survival in superficial BC patients.

摘要

目的

基质金属蛋白酶（MMPs）在黑素细胞中表达，其过度表达与肿瘤的发生、发展和转移有关。在基因水平上，已知功能性启动子多态性可改变基因转录：MMP2 的 -1306C > T 和 -735C > T，以及 MMP8 基因的 799C > T。因此，我们假设启动子区域的 2 个 MMP 单核苷酸多态性的功能性多态性可能会调节北印度人群膀胱癌（BC）进展的风险。

材料和方法

采用基于 PCR 的方法，对 200 例 BC 患者和 200 例年龄匹配、相似种族的无相关健康对照者进行这些多态性的基因分型。采用双侧 χ(2)、Cox 回归评估基因型与各种临床和流行病学因素之间的关系。采用 logistic 回归进行多变量分析，调整年龄和性别等已知 BC 混杂因素。采用 Kaplan-Meier 法进行生存分析，对数秩检验评估生存差异。

结果

MMP2（-1306）TT 基因型和 T 等位基因个体患 BC 的风险更高（P，0.042；OR，2.85；P，0.001；OR，1.76）。CT+TT 个体的这种影响更为明显（P < 0.001；OR，2.61）。在 MMP2（735）中，CT+TT 表现出显著的风险（P，0.034；OR，1.66）。在 MMP8（799）中，TT 基因型观察到风险降低（P，0.006；OR，0.27）。单倍型分析显示，735C-1306T 和 735T-1306C 单倍型个体的风险增加 1.9 倍和 1.5 倍。MMP2-1306CC 与 MMP8-799CT 基因型的组合显示出保护作用。MMP2 1306C > T 的 CT 和 CT+TT 基因型与 BCG 治疗患者的高复发风险相关（HR，4.32；P，0.006 和 HR，2.06；P，0.047），从而降低无复发生存率（CT+TT/CC = 34/45 个月；log rank P，0.039）。