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

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

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.1043297

DOI=10.3389/fgene.2022.1043297

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Recent studies demonstrate that N6-methyladenosine (m<sup>6</sup>A) methylation plays a crucial role in colorectal cancer (CRC). Therefore, we conducted a comprehensive analysis to assess the m<sup>6</sup>A modification patterns and identify m<sup>6</sup>A-modified genes in patients with CRC recurrence.</p><p><bold>Methods:</bold> The m<sup>6</sup>A modification patterns were comprehensively evaluated by the NMF algorithm based on the levels of 27 m<sup>6</sup>A 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 m<sup>6</sup>A scoring scheme was used to explore the m<sup>6</sup>A modification patterns of individual tumors with immune responses. The weighted correlation network analysis and univariable and multivariable Cox regression analyses were applied to identify m<sup>6</sup>A-modified gene signatures. The single-cell expression dataset of CRC samples was used to explore the tumor microenvironment affected by these signatures.</p><p><bold>Results:</bold> Three distinct m<sup>6</sup>A modification patterns with significant recurrence-free survival (RFS) were identified in 804 CRC patients. The TME characterization revealed that the m<sup>6</sup>A modification pattern with longer RFS exhibited robust immune responses. CRC patients were divided into high- and low-score subgroups according to the m<sup>6</sup>A score individually, which was obtained from the m<sup>6</sup>A-related signature genes. The patients with low m<sup>6</sup>A scores had both longer RFS and overall survival (OS) with altered immune cell infiltration. Notably, m<sup>6</sup>A-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.</p><p><bold>Conclusion:</bold> The m<sup>6</sup>A 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 m<sup>6</sup>A-modified genes associated with CRC recurrence, thereby serving as a promising predictive biomarker or therapeutic target for patients with CRC recurrence.</p>