Analysis of m6A Methylation Modification Patterns and Tumor Immune Microenvironment in Breast Cancer.

Menglu Dong,Guang Yang,Wenzhuang Shen,Xingrui Li,Zhifang Yang

doi:10.3389/fcell.2022.785058

Abstract

Increasing evidence indicates that the abnormal expression of N6-methyladenosine (m6A) modification is closely related to the epigenetic regulation of immune response in breast cancer (BC). However, the potential roles of m6A modification in the tumor microenvironment (TME) of BC remain unclear. For addressing this issue, we comprehensively analyzed the m6A modification patterns in 983 samples and correlated these modification patterns with TME immune cell infiltration, based on 23 kinds of m6A regulators. Principal component analysis (PCA) was used to construct the m6A scoring system to quantify the modification pattern of m6A of BC individuals. Consequently, three different m6A modification patterns were identified, and the infiltrating characteristics of TME cells were consistent with the three immune phenotypes, including immune rejection, immune inflammation, and immune desert. Besides, our analysis showed that the prognosis of patients could be predicted by evaluating the m6A modification pattern in the tumor. The low m6Ascore corresponded to increased mutation burden and immune activation, while stroma activation and lack of immune infiltration were observed in high m6Ascore subtypes. In addition, a low m6Ascore was associated with enhanced response to anti-PD-1/PD-L1 immunotherapy. In conclusion, the m6A modification pattern was closely related to the BC immune landscape. This well-validated score model of the m6A modification patterns will provide a valuable tool to depict the tumor immune state and guide effective tumor immunotherapy for combating BC.

Highlights

As the third layer of epigenetics, N6-methyladenosine (m6A) is considered to be the most common modification type in mRNAs and long non-coding RNAs (Alarcón et al, 2015)
Among 23 m6A regulators, LRPPRC, YTHDF1, FMR1, WTAP, YTHDC1, YTHDF3, and RNPA2B1 were mutated in breast cancer (BC), while the other regulatory factors were not mutated
It was found that the copy number variation (CNV) alteration frequency of 23 m6A regulators was prevalent in BC, most of which were with the copy number amplification

Summary

Introduction

As the third layer of epigenetics, N6-methyladenosine (m6A) is considered to be the most common modification type in mRNAs and long non-coding RNAs (lncRNAs) (Alarcón et al, 2015). M6A methylation can affect various aspects of RNA metabolism, including RNA translocation, splicing, stability, and translation into proteins. Similar to DNA and protein modification, m6A modification is a dynamic and reversible process mediated by three different types of regulatory proteins: methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). The demethylases, represented by FTO and ALKBH5, can mediate the m6A removal process that selectively removes methyl codes from specific mRNAs. In addition, the specific m6A-binding proteins, consisting of the YTHDF family (YTHDF1/2/3), YTHDC1/2, eukaryotic initiation factors (eIF or EIF1A), and nuclear heterogeneous riboprotein family (HNRNPA2B1 and HNRNPC), are m6A readers that can recognize and bind to the m6A methylation sites of in RNA, thereby affecting the m6A functions. The present studies on the m6A regulators will help interpret the impact and mechanism of m6A modification in posttranscriptional regulation

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