Multiomics integrative analysis for gene signatures and prognostic values of m⁶A regulators in pancreatic adenocarcinoma: a retrospective study in The Cancer Genome Atlas project

Abstract

N6-methyladenosine(m 6 A) is the most abundant post-transcriptional RNA modification in eukaryotes. However, little is known about its role in pancreatic adenocarcinoma (PAAD). The aim of our study was to identify gene signatures and prognostic values of m 6 A regulators in PAAD. Patients from 3 different datasets with complete genomic and transcriptomic sequencing data were enrolled. Survival analysis for different gene alterations was performed using log-rank tests and Cox regression model. The association between alteration of m 6 A regulators and clinicopathological characteristics was examined using chi-square test. Results showed a high frequency of copy number alterations (CNAs) of m 6 A regulatory genes in PAAD patients, but somatic mutations were rarely happened. CNAs and mutations of m 6 A regulatory genes was associated with patient’s gender, pathologic stage and resected tumor size. Patients with “gain of function” for m 6 A “reader” genes combined with copy number loss of “writers” or “erasers” had worse overall survival (OS) compared with other patterns. Moreover, copy number gain of m 6 A “reader” gene insulin growth factor 2 binding protein 2 ( IGF2BP2) was an independent risk factor for OS (HR = 2.392, 95%CI: 1.392-4.112, p<0.001) and disease-free survival (DFS) (HR = 2.400, 95%CI: 1.236-4.659, p=0.010). Gene Set Enrichment Analysis (GSEA) indicated that IGF2BP2 was correlated with multiple biological processes associated with cancer, of which the most significant processes were relevant to cancer cell cycle, cell immortalization and tumor immunity. To sum up, a significant relationship was found between m 6 A genomic alterations and worse clinical outcomes. These innovative findings are expected to guide further research on the mechanism of m 6 A in PAAD.

The effect of m6A RNA methylation regulators on tumor microenvironment in clear cell renal cell carcinoma

“…Among these dysregulated m6A regulators, we noticed that patients with higher expressions of METTL3, IGF2BP3, WTAP, IGF2BP2 and HNRNPA2B1 had a better prognosis, whereas patients with higher expressions of METTL14, ZC3H13, YHDF3 and YTHDC2 had worse prognosis (Figure .1C). Lobo et al indicated that "writers" were regarded as the main m6A regulators and related with patients' OS in ccRCC [25]. Our present study also con rmed the vital roles of "writers" of METTL3, METTL14, WTAP and ZC3H13 in predication of ccRCC patients' OS.…”

N6-methyladenosine (m6A) in pancreatic cancer: Regulatory mechanisms and future direction

“…For example, overexpression of METTL3 has been associated with poor prognosis in pancreatic cancer [62]. Several studies have reported that IGF2BP2 was markedly overexpressed in PanIN and associated with clinical outcomes, implying that IGF2BP2 might be a potential diagnostic and prognostic biomarker for pancreatic cancer [81][82][83]. Intriguingly, we also found that both m 6 A writer (METTL3 and METTL14) and eraser (FTO) are abnormally upregulated and have a carcinogenic effect in pancreatic cancer.…”

“…Interestingly, higher IGF2BP2 expression was detected in circulating tumor cells than normal hematological cells and normal tissues from the tumor origin [81]. Similarly, another study showed that IGF2BP2 was correlated with clinical outcome and multiple biological processes involved in cancer, of which the most significant processes were associated with cancer cell cycle, immortalization, and tumor immunity [82]. Another study also found that IGF2BP2 promoted cell proliferation and aerobic glycolysis in PDAC by directly binding and stabilizing GLUT1 mRNA [83].…”

“…Recently, several studies have investigated the prognostic value of m 6 A-related mRNA signature and m 6 A regulators in pancreatic cancer using database analysis [82,[103][104][105][106]. For instance, Meng et al provided an mRNA signature that may enhance the prognostic prediction of patients with pancreatic cancer based on the genetic status of m 6 A regulators.…”

Function and clinical significance of N6-methyladenosine in digestive system tumours

“…As a result, these tumour cells become more proliferative and more resistant to drugs [ 130 ]. IGF2BP2 has also been found through TCGA database analysis and various bioinformatics methods to play an important role in m6A modification in PAAD from genomics, transcriptomics, and clinical data perspectives [ 131 ]. The m6A regulatory genes are differentially expressed in PAAD and are closely related to the clinicopathological characteristics of PAAD [ 132 ].…”