Pancreatic cancer is an aggressive cancer of the digestive system with high morbidity and mortality. Data from the National Centre for Health Statistics (NCSH) show a reduction in the occurrence of breast cancer, colorectal cancer, and prostate cancer in the past decade, but the incidence of pancreatic cancer continues to increase and it has become the fourth leading cause of cancer death . Studies have predicted that it could be the second leading cause of cancer death by 2030 . The estimated incidence of pancreatic cancer in the United States in 2020 is around 57,600 with a projected 47,050 deaths, which indicates a mortality above 80% . Furthermore, the 5-year survival rate of pancreatic cancer is 9% and is the lowest across all types of cancer. Pancreatic adenocarcinoma (PAAD) is the most common type of pancreatic cancer, which encompasses up to 85% of pancreatic cancer . While the precise cause and underlying mechanisms of PAAD are still unclear, genetics is an important factor related to tumour development and mutations in DNA or RNA may also drive the initiation of PAAD .
RNA modification is a crucial part of epigenetics, which together with gene and protein modification play an important role in the regulation of cellular processes. Interest in this field has been rising in recent year and according to the data from the MODOMICS update in 2017, 163 different modifications have been identified in RNA molecules so far including N1-methyladenosine, N7-methyladenosine, 5-methylcytosine, pseudouridine, N6,2’-O-dimethyladenosine (m6A) and 2’-O-methylation . In eukaryotes, m6A is the most prevalent and abundant form of mRNA modification, which was identified in the 1970s [5, 6]. m6A is a dynamic and reversible process of mRNA modification and has been widely studied, although the exact mechanism of m6A modification remains unelucidated due to the technical limitations. The formation of m6A is composed of three individual proteins and it is possible to detect these m6A proteins as a reflection of m6A modification. The m6A modulator proteins are classified into three categories: writers, erasers, and readers. Writer proteins mainly include METTL3, METTL14, and WTAP [7–10]. RBM15, ZC3H13, and KIAA1429 have been newly identified and play a role in mediating the formation of the writer protein complex[11–14]. These writer proteins transfer the methyl group from S-adenosyl methionine to the RNA nucleotides. Erasers on the other hand are demethylases and remove the methyl group from the RNA molecule. Members of this group include FTO and ALKBH5 [15, 16]. Finally, reader proteins the members recognise m6A modification and include YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2 [17, 18], and the newly discovered HNRNPC .
m6A plays a vital role in the splicing, translation, and stability of RNA and regulates chromatin state and transcription . This has significant consequences in various human diseases where m6A alterations may enhance heart failure  and influence brain development and function , immune response to viral infection , and bone metabolism . An increasing amount of evidence indicates that m6A RNA methylation modulators are associated with the development and progression of several malignant tumours. In bladder cancer, m6A modulator METTL3 promotes the expression of oncogenes including MYC and AF4 . Furthermore, YTHDF1 has been linked with EIF3C that leads to the occurrence and metastasis of ovarian cancer . Studies have also found that m6A RNA methylation modulators cause genetic alterations across diverse cancer types including mutations and copy number variations . Moreover, m6A RNA methylation modulators have been shown to correlate with clinical parameters and have been utilised as tumour biomarkers to determine the diagnosis and prognosis of several cancer types and monitor the development .
m6A and its modulators are widely studied in hepatocellular cancer, colorectal cancer, and genital and nervous system tumours [26, 29–31]. However, research on m6A RNA methylation modulators in pancreatic cancer is limited. Recently, He et al. demonstrated that ALKBH5 inhibits pancreatic cancer motility by demethylating long non-coding RNA KCNK15-AS1 . Other studies indicate that ALKBH5 decreases WIF-1 RNA methylation and inhibits pancreatic cancer tumorigenesis via the Wnt signalling pathway . In this study, we obtained the expression profiles and clinical data from The Cancer Genome Atlas (TCGA) database of pancreatic cancer to explore the expression of 13 widely reported m6A RNA methylation modulators in PAAD and examine the influence of m6A RNA methylation modulators in the clinical and pathological characteristics of PAAD.