Moreno Victor, Gemignani Federica, Landi Stefano, Gioia-Patricola Lydie, Chabrier Amélie, Blanco Ignacio, González Sara, Guino Elisabet, Capellà Gabriel, Canzian Federico
Institut d'Investigació Biomèdica de Bellvitge, Institut Catala d'Oncologia, Hospitalet, Barcelona, Spain.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2101-8. doi: 10.1158/1078-0432.CCR-05-1363.
We have undertaken a comprehensive study of common polymorphisms in genes of DNA repair, exploring both the risk of developing colorectal cancer and the prognosis of patients.
Subjects from a case-control study (377 cases and 329 controls) designed to assess gene-environment interactions were genotyped by use of an oligonucleotide microarray and the arrayed primer extension technique. Twenty-eight single nucleotide polymorphisms in 15 DNA repair genes were included. The candidate genes belong to different DNA repair pathways: base excision repair (OGG1, LIG3, APEX, POLB, XRCC1, PCNA, and MUTYH), nucleotide excision repair (ERCC1, ERCC2, ERCC4, and ERCC5), double-strand breaks repair (XRCC2, XRCC3, and XRCC9), and reversion repair (MGMT) genes.
Polymorphism OGG1 S326C was associated with an increased risk of colorectal cancer [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.1-5.0], the risk being higher in younger individuals. A haplotype of ERCC1 was associated with increased risk (OR, 2.3; 95% CI, 1.0-5.3). POLB P242R was also associated with decreased risk (OR, 0.23; 95% CI, 0.05-0.99), although the number of variant allele carriers was low. In the univariate analysis, adjusted for age, sex, and Dukes' stage, three polymorphisms were significantly associated with better prognosis: XRCC1 R399Q [hazard ratio (HR), 0.38; 95% CI, 0.17-0.85], XRCC3 T141M (HR, 0.66; 95% CI, 0.45-0.97), and MGMT L84F (HR, 0.14; 95% CI, 0.02-0.99). ERCC1 19007T>C was associated with worse prognosis (HR, 1.51; 95% CI, 1.01-2.27). In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T>C remained significant. These associations were stronger among patients receiving adjuvant chemotherapy.
Although the overall effect of DNA repair genes in colorectal cancer etiology seems limited, their influence in the response to chemotherapy and prognosis may be more relevant. This knowledge may help to clarify the utility of specific adjuvant treatments according to the individual genetic background.
我们对DNA修复基因中的常见多态性进行了全面研究，探讨了患结直肠癌的风险以及患者的预后情况。
通过使用寡核苷酸微阵列和引物延伸技术，对一项旨在评估基因-环境相互作用的病例对照研究中的受试者（377例病例和329例对照）进行基因分型。研究纳入了15个DNA修复基因中的28个单核苷酸多态性。候选基因属于不同的DNA修复途径：碱基切除修复（OGG1、LIG3、APEX、POLB、XRCC1、PCNA和MUTYH）、核苷酸切除修复（ERCC1、ERCC2、ERCC4和ERCC5）、双链断裂修复（XRCC2、XRCC3和XRCC9）以及回复修复（MGMT）基因。
OGG1 S326C多态性与结直肠癌风险增加相关[比值比（OR）为2.3；95%置信区间（95%CI）为1.1 - 5.0]，在年轻个体中风险更高。ERCC1的一个单倍型与风险增加相关（OR为2.3；95%CI为1.0 - 5.3）。POLB P242R也与风险降低相关（OR为0.23；95%CI为0.05 - 0.99），尽管携带变异等位基因的个体数量较少。在单因素分析中，经年龄、性别和Dukes分期校正后，三种多态性与较好的预后显著相关：XRCC1 R399Q[风险比（HR）为0.38；95%CI为0.17 - 0.85]、XRCC3 T141M（HR为0.66；95%CI为0.45 - 0.97）和MGMT L84F（HR为0.14；95%CI为0.02 - 0.99）。ERCC1 19007T>C与较差的预后相关（HR为1.51；95%CI为l.01 - 2.27）。在多因素分析中，只有XRCC1 R399Q和ERCC1 19007T>C仍然具有显著性。这些关联在接受辅助化疗的患者中更强。
尽管DNA修复基因在结直肠癌病因学中的总体作用似乎有限，但其在化疗反应和预后方面的影响可能更为重要。这一认识可能有助于根据个体遗传背景阐明特定辅助治疗的效用。
