Identification of genes modified by N6-methyladenosine in patients with colorectal cancer recurrence

Qianru Zhu; Xingxing Huang; Shuxian Yu; Lan Shou; Ruonan Zhang; Han Xie; Zimao Liang; Xueni Sun; Jiao Feng; Ting Duan; Mingming Zhang; Yu Xiang; Xinbing Sui; Weiwei Jin; Lili Yu; Qibiao Wu

doi:10.3389/fgene.2022.1043297

Identification of genes modified by N6-methyladenosine in patients with colorectal cancer recurrence

Front Genet. 2022 Oct 17:13:1043297. doi: 10.3389/fgene.2022.1043297. eCollection 2022.

Authors

Qianru Zhu^{1

2

3

4}, Xingxing Huang^{1

2

3

4}, Shuxian Yu^{2

3

4}, Lan Shou^{2

3

4}, Ruonan Zhang^{1

2

3

4}, Han Xie^{1

2

3}, Zimao Liang^{1

2

3

4}, Xueni Sun^{2

3

4}, Jiao Feng^{2

3

4}, Ting Duan^{2

3

4}, Mingming Zhang^{2

3

4}, Yu Xiang^{2

3

4}, Xinbing Sui^{1

2

3

4

5

6}, Weiwei Jin^{6

7}, Lili Yu¹, Qibiao Wu^{1

2

3

5}

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
² School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China.
³ Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong University of Technology, Guangzhou, Guangdong, China.
⁴ Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China.
⁵ Zhuhai MUST Science and Technology Research Institute, Zhuhai, Guangdong, China.
⁶ Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
⁷ Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, China.

Abstract

Background: Recent studies demonstrate that N6-methyladenosine (m⁶A) methylation plays a crucial role in colorectal cancer (CRC). Therefore, we conducted a comprehensive analysis to assess the m⁶A modification patterns and identify m⁶A-modified genes in patients with CRC recurrence. Methods: The m⁶A modification patterns were comprehensively evaluated by the NMF algorithm based on the levels of 27 m⁶A regulators, and tumor microenvironment (TME) cell-infiltrating characteristics of these modification patterns were systematically assessed by ssGSEA and CIBERSORT algorithms. The principal component analysis algorithm based on the m⁶A scoring scheme was used to explore the m⁶A modification patterns of individual tumors with immune responses. The weighted correlation network analysis and univariable and multivariable Cox regression analyses were applied to identify m⁶A-modified gene signatures. The single-cell expression dataset of CRC samples was used to explore the tumor microenvironment affected by these signatures. Results: Three distinct m⁶A modification patterns with significant recurrence-free survival (RFS) were identified in 804 CRC patients. The TME characterization revealed that the m⁶A modification pattern with longer RFS exhibited robust immune responses. CRC patients were divided into high- and low-score subgroups according to the m⁶A score individually, which was obtained from the m⁶A-related signature genes. The patients with low m⁶A scores had both longer RFS and overall survival (OS) with altered immune cell infiltration. Notably, m⁶A-modified genes showed significant differences related to the prognosis of CRC patients in the meta-GEO cohort and TCGA cohort. Single-cell expression indicated that ALVRL1 was centrally distributed in endothelial tip cells and stromal cells. Conclusion: The m⁶A modification plays an indispensable role in the formation of TME diversity and complexity. Importantly, the signatures (TOP2A, LRRC58, HAUS6, SMC4, ACVRL1, and KPNB1) were identified as m⁶A-modified genes associated with CRC recurrence, thereby serving as a promising predictive biomarker or therapeutic target for patients with CRC recurrence.

Keywords: colorectal cancer; m6A methylation modification; overall survival; recurrence; tumor immune microenvironment.