Prognostic Value of N6-Methyladenosine-Related lncRNAs in Early-Stage Colorectal Cancer: Association With Immune Cell Infiltration and Chemotherapeutic Drug Sensitivity

Zhizhong Xiong; Xianzhe Li; Shi Yin; Minghao Xie; Chaobin Mao; Fengxiang Zhang; Huaxian Chen; Longyang Jin; Lei Lian

doi:10.3389/fmolb.2021.724889

Prognostic Value of N6-Methyladenosine-Related lncRNAs in Early-Stage Colorectal Cancer: Association With Immune Cell Infiltration and Chemotherapeutic Drug Sensitivity

Front Mol Biosci. 2021 Oct 12:8:724889. doi: 10.3389/fmolb.2021.724889. eCollection 2021.

Authors

Zhizhong Xiong^{1

2}, Xianzhe Li^{1

2}, Shi Yin^{1

2}, Minghao Xie^{1

2}, Chaobin Mao², Fengxiang Zhang¹, Huaxian Chen^{1

2}, Longyang Jin¹, Lei Lian^{1

2}

Affiliations

¹ Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Abstract

Purpose: Accumulating evidence indicates that N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) play a crucial role in the occurrence and development of several cancers. We aimed to explore the potential role of m6A-related lncRNA signatures in predicting prognosis for early-stage (stages I and II) colorectal cancer (CRC). Methods: m6A-related lncRNA data were obtained from The Cancer Genome Atlas. Univariate Cox regression analysis was used to screen for prognostic m6A-related lncRNAs. Immune characteristics were analyzed in different subgroups created via unsupervised clustering analysis. Next, patients were randomly divided into training and test cohorts. In the training cohort, least absolute shrinkage and selection operator (LASSO) regression was performed to establish a prognostic model. The predictive value of the signature was evaluated in the training and test cohorts. Drug sensitivity was also examined. Results: A total of 1,478 m6A-related lncRNAs were identified. Two subgroups were created based on the expression of seven prognostic m6A-related lncRNAs. Prognosis was worse for cluster 1 than for cluster 2, and cluster 1 was characterized by increased numbers of M2 macrophages, decreased numbers of memory B cells, and higher expression of checkpoint genes when compared with cluster 2. Five m6A-related lncRNAs were selected to establish a risk prediction signature via LASSO regression. The 3 years overall survival (OS) was higher in the low-risk group than in the high-risk group. The area under the curve at 1, 2, and 3 years was 0.929, 0.954, and 0.841 in the training cohort and 0.664, 0.760, and 0.754 in the test cohort, respectively. Multivariate Cox regression analysis suggests that the risk score was an independent predictor of OS in both the training and test cohorts. A prognostic nomogram based on the five m6A-related lncRNAs and their clinical features was built and verified. The high-risk group was more sensitive to chemotherapeutic drugs (camptothecin and cisplatin) than the low-risk group. Conclusion: We identified two molecular subgroups of early-stage CRC with unique immune features based on seven prognostic m6A-related lncRNAs. Subsequent analyses demonstrated the usefulness of a five m6A-related lncRNA signature as a potential indicator of prognosis in patients with early-stage CRC.

Keywords: N6-methyladenosine; early-stage colorectal cancer; long non-coding RNA; nomogram; prognosis.