Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Department of Automation and Key Laboratory of China MOE for System Control and Information Processing, Shanghai Jiao Tong University, Shanghai, China.
Transl Res. 2020 May;219:30-44. doi: 10.1016/j.trsl.2020.02.004. Epub 2020 Feb 13.
Accurately prognostic evaluation of patients with stage I-II pancreatic ductal adenocarcinoma (PDAC) is of importance to treatment decision and patient management. Most previously reported prognostic signatures were based on risk scores summarized from quantitative expression measurements of signature genes, which are susceptible to experimental batch effects and impractical for clinical applications. Based on the within-sample relative expression orderings of genes, we developed a robust qualitative transcriptional prognostic signature, consisting of 64 gene pairs (64-GPS), to predict the overall survival (OS) of 161 stage I-II PDAC patients in the training dataset who were treated with surgery only. Samples were classified into the high-risk group when at least 25 of 64 gene pairs suggested it was at high risk. The signature was successfully validated in 324 samples from 6 independent datasets produced by different laboratories. All samples in the low-risk group had significantly better OS than samples in the high-risk group. Multivariate Cox regression analyses showed that the 64-GPS remained significantly associated with the OS of patients after adjusting available clinical factors. Transcriptomic analysis of the 2 prognostic subgroups showed that the differential expression signals were highly reproducible in all datasets, whereas the differences between samples grouped by the TNM staging system were weak and irreproducible. The epigenomic analysis showed that the epigenetic alternations may cause consistently transcriptional changes between the 2 different prognostic groups. The genomic analysis revealed that mutation‑induced disturbances in several key genes, such as LRMDA, MAPK10, and CREBBP, might lead to poor prognosis for PDAC patients. Conclusively, the 64-GPS can robustly predict the prognosis of patients with stage I-II PDAC, which provides theoretical basis for clinical individualized treatment.
准确评估 I 期-II 期胰腺导管腺癌 (PDAC) 患者的预后对于治疗决策和患者管理非常重要。大多数先前报道的预后标志物是基于对标志物基因的定量表达测量的风险评分汇总得出的，这些评分容易受到实验批次效应的影响，且不适合临床应用。基于基因的样本内相对表达顺序，我们开发了一种稳健的定性转录预后标志物，由 64 对基因（64-GPS）组成，用于预测仅接受手术治疗的 161 名 I 期-II 期 PDAC 患者的总生存期 (OS)。当至少 25 对 64 个基因对提示为高风险时，样本被归类为高危组。该标志物在 6 个独立实验室产生的 324 个样本中得到了成功验证。低危组的所有样本的 OS 明显优于高危组的样本。多变量 Cox 回归分析表明，在调整了可用的临床因素后，64-GPS 仍然与患者的 OS 显著相关。对 2 个预后亚组的转录组分析表明，在所有数据集上，差异表达信号高度可重现，而根据 TNM 分期系统分组的样本之间的差异较弱且不可重现。表观基因组分析表明，表观遗传改变可能导致 2 个不同预后组之间的转录变化一致。基因组分析显示，LRMDA、MAPK10 和 CREBBP 等几个关键基因的突变诱导干扰可能导致 PDAC 患者预后不良。总之，64-GPS 可以稳健地预测 I 期-II 期 PDAC 患者的预后，为临床个体化治疗提供了理论依据。
