Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
EBioMedicine. 2018 Jul;33:82-87. doi: 10.1016/j.ebiom.2018.06.028. Epub 2018 Jul 6.
Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC.
A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method.
We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223.
This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation.
全基因组关联研究（GWAS）已经在亚洲人群中鉴定出了几个胃癌（GC）易感性位点，但它们对疾病结局的影响尚不清楚。本研究旨在探讨这些 GWAS 鉴定的遗传变异是否可以作为 GC 的稳健预后生物标志物。
使用一个包括中国人群中 2432 例 GC 患者的多阶段临床队列，来鉴定 GWAS 鉴定的风险变异与 GC 总生存期之间的关联。使用 Cox 回归分析计算危险比（HRs）和 95%置信区间（CIs），并通过对数秩检验和 Kaplan-Meier 方法计算对数秩 P 值。
我们发现 PLCE1 中的 rs2274223 A>G 与训练集（P=0.011）中的 GC 生存增加相关，在验证集 1（P=0.045）中独立复制，但在验证集 2 中没有。来自接收者操作特征（ROC）曲线的曲线下面积（AUC）显示出这种与发病年龄相关的临床相关性，尤其是在早发病例亚组中。此外，当将 rs2274223 的遗传效应纳入估计时，发现整体生存预测得到了显著改善；这一结果也得到了预后列线图的支持。此外，PLCE1 表达较低的患者生存期更长，这可能是由于 rs2274223 的功能影响。
这项初步研究表明，PLCE1 中的 GWAS 鉴定的遗传变异可能作为 GC 生存的潜在生物标志物。需要更大的样本量进行进一步的复制研究。
