A Novel Signature Based on m6A RNA Methylation Regulators Reveals Distinct Prognostic Subgroups and Associates with Tumor Immunity of Patients with Pancreatic Neuroendocrine Neoplasms

Xianlong Chen; Shengwei Mo; Liju Zong; Shuangni Yu; Zhaohui Lu; Jie Chen

doi:10.1159/000525228

A Novel Signature Based on m6A RNA Methylation Regulators Reveals Distinct Prognostic Subgroups and Associates with Tumor Immunity of Patients with Pancreatic Neuroendocrine Neoplasms

Neuroendocrinology. 2022;112(12):1187-1199. doi: 10.1159/000525228. Epub 2022 May 24.

Authors

Xianlong Chen¹, Shengwei Mo¹, Liju Zong¹, Shuangni Yu¹, Zhaohui Lu¹, Jie Chen¹

Affiliation

¹ Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Introduction: The RNA N6-methyladenosine (m6A) regulators play a crucial role in tumorigenesis and could be indicators of prognosis and therapeutic targets in various cancers. However, the expression status and prognostic value of m6A regulators have not been studied in pancreatic neuroendocrine neoplasms (PanNENs). We aimed to investigate the expression patterns and prognostic value of m6A regulators and assess their correlations with immune checkpoints and infiltrates in PanNENs.

Methods: Immunohistochemistry was performed for 15 m6A regulators and immune markers using tissue microarrays obtained from 183 patients with PanNENs. The correlation between m6A protein expression and clinicopathological parameters with recurrence-free survival (RFS) was examined using a random survival forest, Cox regression model, and survival tree analysis.

Results: Among the 15 m6A proteins, high expression of YTHDF2 (p < 0.001) and HNRNPC (p = 0.006) was found to be significantly associated with recurrence and served as independent risk factors in multivariate analysis. High YTHDF2 expression was associated with higher number of CD3+ T cells (p = 0.003), whereas high HNRNPC expression was significantly correlated with the expression of PD-L1 (p = 0.039). A YTHDF2-based signature was determined, including five patterns from survival tree analysis: patients with the LNnegYTHDF2high signature had a 5-year RFS rate of 92.1%, whereas patients with LNposTumorSize＜2.5 cm signature had the worst 5-year RFS rate of 0% (p < 0.001). The area under receiver operating characteristic curve was 0.870 (95% confidence interval: 0.762-0.915) for the YTHDF2-based signature. The C-index was 0.978, suggesting good discrimination ability; moreover, the risk score of recurrence served as an independent prognostic factor indicating shorter RFS.

Conclusions: YTHDF2 appears to serve as a promising prognostic biomarker and therapeutic target. A YTHDF2-based signature can identify distinct subgroups, which may be helpful to strategize personalized postoperative monitoring.

Keywords: Immune markers; N6-methyladenosine methylation regulators; Pancreatic neuroendocrine neoplasms; Postoperative surveillance; Recurrence.

The Author(s). Published by S. Karger AG, Basel.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine* / metabolism
Humans
Methylation
Multivariate Analysis
Neoplasms*
Prognosis
RNA / genetics
RNA / metabolism

Substances

Adenosine
RNA

Grants and funding

This work was supported by grants from the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-2016-I2M-1–001), the National Scientific Data Sharing Platform for Population and Health (NCMI–YF01N–201906), and the National Natural Science Foundation of China (Nos. 81672648).