Research Paper Volume 12, Issue 20 pp 20587—20610
Multiomics integrative analysis for gene signatures and prognostic values of m6A regulators in pancreatic adenocarcinoma: a retrospective study in The Cancer Genome Atlas project
- 1 Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
- 2 Medical College of Xiangya, Central South University, Changsha 410013, Hunan Province, China
- 3 Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
Received: February 27, 2020 Accepted: August 3, 2020 Published: October 20, 2020
https://doi.org/10.18632/aging.103942How to Cite
Copyright: © 2020 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
N6-methyladenosine(m6A) 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 m6A 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 m6A regulators and clinicopathological characteristics was examined using chi-square test. Results showed a high frequency of copy number alterations (CNAs) of m6A regulatory genes in PAAD patients, but somatic mutations were rarely happened. CNAs and mutations of m6A regulatory genes was associated with patient’s gender, pathologic stage and resected tumor size. Patients with “gain of function” for m6A “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 m6A “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 m6A genomic alterations and worse clinical outcomes. These innovative findings are expected to guide further research on the mechanism of m6A in PAAD.
Abbreviations
PC: pancreatic cancer; ADEX: aberrantly differentiated endocrine exocrine; TCGA: the cancer genome atlas; PPI: protein-protein interaction; TCGA_PAAD: pancreatic adenocarcinoma cohort from TCGA project; m6A: N6-methyladenosine; PAAD: pancreatic adenocarcinoma; CNA: copy number alteration; EIF3A: eukaryotic initiation factor 3a; HNRNPA2B1: heterogeneous nuclear ribonucleoprotein A2B1; KRAS: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; TP53: tumor protein p53; FTO: fat mass and obesity associated gene; RBM15: RNA Binding Motif Protein 15; ZC3H13: Zinc Finger CCCH-Type Containing 13; YTHDC: YTH Domain Containing family; YTHDF: YTH N6-Methyladenosine RNA Binding Protein family; GTEx: Genotype-Tissue Expression (GTEx) database; ccRCC: clear cell renal cell carcinoma; AML: acute myeloid leukemia; RBP: RNA binding protein; IGF2BP2: Insulin-Like Growth Factor 2 mRNA-Binding Protein 2; GSEA: Gene Set Enrichment Analysis; METTL3: methyltransferase like 3; ALKBH5: alkB homolog 5; WTAP: WT1 associated protein; VIRMA: vir like m m6A methyltransferase associated; OS: overall survival; DFS: disease-free survival; DANCR: Differentiation Antagonizing Non-Protein Coding RNA; lnc-DANCR: long non-coding RNA DANCR.