Smith Christopher G, Fisher David, Harris Rebecca, Maughan Timothy S, Phipps Amanda I, Richman Susan, Seymour Matthew, Tomlinson Ian, Rosmarin Dan, Kerr David, Chan Andrew T, Peters Ulrike, Newcomb Polly A, Idziaszczyk Shelley, West Hannah, Meade Angela, Kaplan Richard, Cheadle Jeremy P
Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
Clin Cancer Res. 2015 Aug 1;21(15):3453-61. doi: 10.1158/1078-0432.CCR-14-3136. Epub 2015 Apr 14.
Genome-wide association studies have identified numerous loci associated with colorectal cancer risk. Several of these have also been associated with patient survival, although none have been validated. Here, we used large independent training and validation cohorts to identify robust prognostic biomarkers for colorectal cancer.
In our training phase, we analyzed 20 colorectal cancer-risk SNPs from 14 genome-wide associated loci, for their effects on survival in 2,083 patients with advanced colorectal cancer. A Cox survival model was used, stratified for treatment, adjusted for known prognostic factors, and corrected for multiple testing. Three SNPs were subsequently analyzed in an independent validation cohort of 5,552 colorectal cancer patients. A validated SNP was analyzed by disease stage and response to treatment.
Three variants associated with survival in the training phase; however, only rs9929218 at 16q22 (intron 2 of CDH1, encoding E-cadherin) was significant in the validation phase. Patients homozygous for the minor allele (AA genotype) had worse survival (training phase HR, 1.43; 95% confidence intervals; CI, 1.20-1.71, P = 5.8 × 10(-5); validation phase HR, 1.18; 95% CI, 1.01-1.37, P = 3.2 × 10(-2); combined HR, 1.28; 95% CI, 1.14-1.43, P = 2.2 × 10(-5)). This effect was independent of known prognostic factors, and was significant amongst patients with stage IV disease (P = 2.7 × 10(-5)). rs9929218 was also associated with poor response to chemotherapy (P = 3.9 × 10(-4)).
We demonstrate the potential of common inherited genetic variants to inform patient outcome and show that rs9929218 identifies approximately 8% of colorectal cancer patients with poor prognosis. rs9929218 may affect CDH1 expression and E-cadherin plays a role in epithelial-to-mesenchymal transition providing a mechanism underlying its prognostic potential. Clin Cancer Res; 21(15); 3453-61. ©2015 AACR.
全基因组关联研究已经确定了许多与结直肠癌风险相关的基因座。其中一些基因座也与患者生存率相关，尽管尚未得到验证。在此，我们使用大型独立的训练和验证队列来确定结直肠癌可靠的预后生物标志物。
在我们的训练阶段，我们分析了来自14个全基因组关联基因座的20个结直肠癌风险单核苷酸多态性（SNP），以研究它们对2083例晚期结直肠癌患者生存的影响。使用Cox生存模型，按治疗进行分层，对已知的预后因素进行校正，并对多重检验进行校正。随后在一个包含5552例结直肠癌患者的独立验证队列中分析了三个SNP。对一个经过验证的SNP按疾病分期和对治疗的反应进行分析。
在训练阶段有三个变异与生存相关；然而，在验证阶段只有位于16q22的rs9929218（CDH1基因第2内含子，编码E-钙黏蛋白）具有显著意义。次要等位基因纯合子（AA基因型）的患者生存率较差（训练阶段风险比[HR]，1.43；95%置信区间[CI]，1.20 - 1.71，P = 5.8×10⁻⁵；验证阶段HR，1.18；95% CI，1.01 - 1.37，P = 3.2×10⁻²；合并HR，1.28；95% CI，1.14 - 1.43，P = 2.2×10⁻⁵）。这种效应独立于已知的预后因素，并且在IV期疾病患者中具有显著意义（P = 2.7×10⁻⁵）。rs9929218也与化疗反应不佳相关（P = 3.9×10⁻⁴）。
我们证明了常见的遗传变异对预测患者预后的潜力，并表明rs9929218可识别约8%预后不良的结直肠癌患者。rs9929218可能影响CDH1表达，且E-钙黏蛋白在上皮-间质转化中起作用，这为其预后潜力提供了一种潜在机制。《临床癌症研究》；21(15)；3453 - 61。©2015美国癌症研究协会。
