Construction of a DDR-related signature for predicting of prognosis in metastatic colorectal carcinoma

Maohua Wei; Junyan Su; Jiali Zhang; Siyao Liu; Jia Ma; Xiang Peng Meng

doi:10.3389/fonc.2023.1043160

Construction of a DDR-related signature for predicting of prognosis in metastatic colorectal carcinoma

Front Oncol. 2023 Feb 1:13:1043160. doi: 10.3389/fonc.2023.1043160. eCollection 2023.

Authors

Maohua Wei¹, Junyan Su², Jiali Zhang², Siyao Liu², Jia Ma³, Xiang Peng Meng⁴

Affiliations

¹ Department of General Surgery, Dalian Medical University, Dalian, China.
² Department of Scientific Research Projects, ChosenMed Technology Co. Ltd., Beijing, China.
³ Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
⁴ Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.

Abstract

Background: Colorectal cancer (CRC) is the third most prevalent malignancy and the one of most lethal cancer. Metastatic CRC (mCRC) is the third most common cause of cancer deaths worldwide. DNA damage response (DDR) genes are closely associated with the tumorigenesis and development of CRC. In this study, we aimed to construct a DDR-related gene signature for predicting the prognosis of mCRC patients.

Methods: The gene expression and corresponding clinical information data of CRC/mCRC patients were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. A prognostic model was obtained and termed DDRScore by the multivariate Cox proportional hazards regression in the patients with mCRC. The Kaplan-Meier (K-M) and Receiver Operating Characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed for patients between the high-DDRscore and low-DDRscore groups.

Results: We constructed a prognostic model consisting of four DDR-related genes (EME2, MSH4, MLH3, and SPO11). Survival analysis showed that patients in the high-DDRscore group had a significantly worse OS than those in the low-DDRscore group. The area under the curve (AUC) value of the ROC curve of the predictive model is 0.763 in the training cohort GSE72970, 0.659 in the stage III/IV colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) data portal, and 0.639 in another validation cohort GSE39582, respectively. GSEA functional analysis revealed that the most significantly enriched pathways focused on nucleotide excision repair, base excision repair, homologous recombination, cytokine receptor interaction, chemokine signal pathway, cell adhesion molecules cams, ECM-receptor interaction, and focal adhesion.

Conclusion: The DDRscore was identified as an independent prognostic and therapy response predictor, and the DDR-related genes may be potential diagnosis or prognosis biomarkers for mCRC patients.

Keywords: DDRscore; metastatic colorectal cancer; predictor; prognostic; therapy response.