State Key Laboratory of Cancer Biology, Cell Engineering Research Centre, Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
Eur J Cancer. 2011 Jul;47(11):1699-707. doi: 10.1016/j.ejca.2011.02.004. Epub 2011 Mar 12.
Extensive evidence has suggested that risk factors of cancer development may also modulate cancer clinical outcome. Recent genome-wide association (GWA) studies identified several single nucleotide polymorphisms (SNPs) predisposing to colorectal cancer (CRC). Given the pivotal importance of these variants in CRC, we sought to evaluate their associations with clinical outcomes of the disease.
In a well-characterised cohort including 380 Chinese CRC patients, we genotyped seven SNPs identified in previous multi-stage GWA studies and analysed their associations with patient recurrence and survival.
One SNP on chromosome 15q13, rs4779584 was associated with reduced risk of death with a hazard ratio (HR) of 0.33 (95% confidence interval [CI] 0.15-0.72, P = 0.007). Another SNP in a gene-desert region on chromosome 10p14, rs10795668, was associated with a reduced risk of recurrence with an HR of 0.55 (95% CI 0.30-1.00, P = 0.05). In a stratified analysis, this association was only evident in patients receiving chemotherapy (HR = 0.32, 95% CI 0.14-0.78, P = 0.01, log rank P = 0.004), but not in those without chemotherapy (HR = 1.08, 95% CI 0.43-2.73, P = 0.87, log rank P = 0.66). Moreover, we found that the effects of chemotherapy on CRC recurrence was only evident in patients with the variant-containing genotypes (HR = 0.35, 95% CI 0.13-0.94, P = 0.04) but not in those with the wild-type genotype of rs10795668. Further analyses indicated a borderline significant interaction effect (P interaction = 0.05) between rs10795668 and chemotherapy on patient recurrence.
Our data suggested that rs10795668, a CRC susceptibility variant identified by GWA studies, might be used as a biomarker to identify CRC patients with high risk of recurrence after chemotherapy.
大量证据表明，癌症发生的风险因素也可能调节癌症的临床结局。最近的全基因组关联（GWA）研究鉴定了几个导致结直肠癌（CRC）的单核苷酸多态性（SNP）。鉴于这些变异在 CRC 中的重要性，我们试图评估它们与疾病临床结局的关系。
在一个包括 380 名中国 CRC 患者的特征明确的队列中，我们对之前多阶段 GWA 研究中鉴定的七个 SNP 进行了基因分型，并分析了它们与患者复发和生存的关系。
染色体 15q13 上的一个 SNP（rs4779584）与死亡风险降低相关，风险比（HR）为 0.33（95%置信区间 [CI] 0.15-0.72，P=0.007）。染色体 10p14 上一个基因缺失区域的另一个 SNP（rs10795668）与复发风险降低相关，HR 为 0.55（95%CI 0.30-1.00，P=0.05）。在分层分析中，这种关联仅在接受化疗的患者中明显（HR=0.32，95%CI 0.14-0.78，P=0.01，对数秩 P=0.004），而在未接受化疗的患者中不明显（HR=1.08，95%CI 0.43-2.73，P=0.87，对数秩 P=0.66）。此外，我们发现化疗对 CRC 复发的影响仅在携带变异基因型的患者中明显（HR=0.35，95%CI 0.13-0.94，P=0.04），而在 rs10795668 野生型基因型的患者中不明显。进一步的分析表明，rs10795668 与化疗对患者复发的交互作用有边缘显著性（P 交互=0.05）。
我们的数据表明，GWA 研究中鉴定的 CRC 易感性变异 rs10795668 可作为生物标志物，用于识别化疗后复发风险高的 CRC 患者。
