N6-methyladenosine (m6A) regulatory gene divides hepatocellular carcinoma into three subtypes

Jie Wei; Da Lang Fang; Weijie Zhou; Yong Fei He

doi:10.21037/jgo-21-378

N6-methyladenosine (m6A) regulatory gene divides hepatocellular carcinoma into three subtypes

J Gastrointest Oncol. 2021 Aug;12(4):1860-1872. doi: 10.21037/jgo-21-378.

Authors

Jie Wei¹, Da Lang Fang², Weijie Zhou³, Yong Fei He⁴

Affiliations

¹ Department of Hematology, Baise People's Hospital, Baise, China.
² Department of Breast and Thyroid Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
³ Clinical Laboratory, Baise People's Hospital, Baise, China.
⁴ Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nannning, China.

Abstract

Background: The N6-methyladenosine (m6A) plays an important role in epigenetic modification and tumor progression, but the modulations of m6A in hepatocellular carcinoma (HCC) have not been determined while the relationship between m6A regulation and immune cell infiltration remains unclear.

Methods: This study investigated the modification patterns of m6A by analyzing HCC samples from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) dataset, and performed molecular typing based on the characteristics of immune cell infiltration. The m6Ascore was also constructed to quantify m6A modifications and predict the immunotherapy response and prognosis of HCC patients.

Results: Of the 364 samples, 31 (8.52%) were genetically altered in the m6A regulatory gene, with the highest frequency of mutations in HNRNPC, ZC3H13, and LRPPRC. Three distinct molecular subtypes of m6A were identified in 590 HCC samples, which were associated with different immune cell infiltrates: immunodepletion type, immune activation type, and immune immunity type. According to the construction of the m6Ascore system in the m6A genotype, HCC patients could be divided into high and low groups. The m6A modified pattern, characterized by immune immunity and immune failure, showed a lower score and a better prognosis. However, the immune-activated type of m6A had a higher score and a poorer prognosis. Further analysis showed that the m6Ascore was correlated with tumor mutation burden (TMB), and the higher the TMB, the worse the prognosis. m6Ascore was also correlated with the expression of cytotoxic T-lymphocyte-associated protein 4 (CTAL-4), and the higher the score, the higher the expression of HCC in patients.

Conclusions: HCC has a unique m6A modification pattern, and 3 different m6A subtypes help to classify HCC, provide knowledge of drug regimens for immunotherapy, and can be used to predict treatment response and prognosis.

Keywords: N6-methyladenosine (m6A); hepatocellular carcinoma (HCC); immune profiles; subtypes.