J Cancer 2020; 11(21):6299-6318. doi:10.7150/jca.47629

Research Paper

Development and validation of a metastasis-related Gene Signature for predicting the Overall Survival in patients with Pancreatic Ductal Adenocarcinoma

Mengwei Wu, Xiaobin Li, Rui Liu, Hongwei Yuan, Wei Liu, Ziwen Liu

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

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Citation:
Wu M, Li X, Liu R, Yuan H, Liu W, Liu Z. Development and validation of a metastasis-related Gene Signature for predicting the Overall Survival in patients with Pancreatic Ductal Adenocarcinoma. J Cancer 2020; 11(21):6299-6318. doi:10.7150/jca.47629. Available from http://www.jcancer.org/v11p6299.htm

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal, aggressive cancer characterized by invasiveness and metastasis. In this study, we aimed to propose a gene prediction model based on metastasis-related genes (MTGs) to more accurately predict PDAC prognosis.

Methods: Differentially expressed MTGs (DE-MTGs) were identified via integrated analysis of gene expression omnibus (GEO) datasets and Human Cancer Metastasis Database (HCMDB). Overall survival (OS) related DE-MTGs were then identified and a prognostic gene signature was established using Lasso-Cox regression with TCGA-PAAD datasets. Tumor immunity was analyzed using ESTIMATE and CIBERSORT algorithms. Finally, a nomogram predicting 1-year, 2-year, and 3-year OS of PDAC patients was established based on the prognostic gene signature and relevant clinical parameters using a stepwise Cox regression model.

Results: A total of 36 DE-MTGs related to OS were identified in PDAC. Consequently, an MTG-based gene signature comprising of RACGAP1, RARRES3, TPX2, MMP28, GPR87, KIF14, and TSPAN7 was established to predict the OS of PDAC. The MTG-based gene signature was able to distinguish high-risk patients with significantly poorer prognosis and accurately predict OS of PDAC in both the training and external validation datasets. Cox regression analysis indicated that the MTG-based gene signature was an independent prognostic factor in PDAC. The gene set enrichment analysis (GSEA) showed that molecular alterations in the high-risk group were associated with multiple oncological pathways. Moreover, analysis of tumor immunity revealed significantly higher levels of follicular helper T cells and M0 macrophage infiltration, and lower levels of infiltrating naïve B cells, CD8 T cells, monocytes, and resting dendritic cells in the high-risk group. Immune cell infiltration levels were significantly associated with the expression of the seven DE-MTGs. Finally, a nomogram was established by incorporating the prognostic gene signature and clinical parameters, which was superior to the AJCC staging system in predicting the OS of PDAC patients.

Conclusions: The DE-MTGs we identified were closely associated with the progress and prognosis of PDAC and are potential therapeutic targets. The MTG-based gene signature and nomogram may serve to improve the individualized prediction of survival, assisting in clinical decision-making.

Keywords: Gene Expression Omnibus, The Cancer Genome Atlas Program, pancreatic ductal adenocarcinoma, overall survival, nomogram