Vaishnavi Kardale, Bioinformatics Centre, Savitribai Phule Pune University
Pancreatic cancer is the seventh leading cause of cancer death in both men and women alike. This happens mainly due to a poor prognosis. Pancreatic cancer is not easily diagnosed at an early stage because there aren’t any noticeable signs in the early stage of pancreatic cancer. The position of the pancreas, hidden behind other organs like the stomach, small intestine, liver, gallbladder, and spleen also seems to play a role.
When symptoms of pancreatic cancer are present, they are similar to signs and symptoms from many other diseases. According to the data from National Centre for Health Statistics, a decreasing trend has been observed in the occurrence of breast cancer, colorectal cancer, and prostate cancer in the past decade; however, the incidence of pancreatic cancer continues to increase. In the year 2020, the mortality rate of pancreatic cancer was above 80%. Many experts predict that by 2030 pancreatic cancer could be the second leading cause of cancer death. Cancer researchers around the world have been challenged with these alarming death rates. Epigenetic modifications are described as an essential player in cancer progression.
What is epigenetic modification?
Epigenetics controls heritable genetic expression without modifying the DNA sequence. Some of the most common epigenetic modifications include DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. Among these, methylation modification is extremely important in both DNA and RNA. N6 -methyladenosine (m6A) is the most prevalent epigenetic modification observed in eukaryotic RNA. It is a reversible type of mRNA modification; however, its mechanism is poorly understood.
M6A modifications are carried out by three classes: writers, readers, and erasers. The writer protein transfers the methyl group from S-adenosyl methionine to the RNA nucleotides and includes METTL3, METTL14, WTAP, CBLL1, and METTL16. On the other hand, erasers remove the methyl group from the RNA. The demethylases that make up the erasers include FTO and ALKBH5. The m6A modifications are recognized by a class of proteins called readers that include YTHDF1/2/3 and YTHDC1/2.
m6A modifications have a significant role in various human diseases like heart failure, influence brain development and function, immune response to viral infection, and bone metabolism. Many evidence suggests that m6A RNA methylation modulators are associated with the development and progression of several malignant tumors. Studies have shown that m6A RNA methylation modulators correlate with clinical parameters and hence have been used as tumor biomarkers to diagnose several cancer types and monitor their progression. In recent research published in BMC Cancer, Wang et al. integrated the gene expression profile from The Cancer Genome Atlas (TCGA) and GTEx database, extracted the expression of 28 widely reported m6A RNA methylation modulators from 140 patients with pancreatic adenocarcinoma.
How was the research carried out?
Having collected the data, the researchers compared the difference in expression of the 28 m6A RNA methylation modulators between tumor samples and healthy samples by the Wilcoxon test. LASSO COX regression was used to analyze the relationship between expression and clinical characteristics by univariate and multivariate regression. A risk score was assigned based on the expression of select few m6A RNA methylation modulators. Using the CIBERSORT algorithm, bioinformatics analysis was carried out to explore the association between the m6Ascore and the immune cells.
What did the study find?
The study found that 28 m6A RNA methylation modulators were upregulated in patients with Pancreatic adenocarcinoma except for MTEEL3. The researchers were able to establish an m6A prognosis model. KIAA1429, IGF2BP3, METTL3, EIF3H, and LRPPRC were used to predict the prognosis of patients with pancreatic adenocarcinoma. A higher score indicated a lower overall survival.
Patients who had a high m6Ascore had lower infiltration of Tregs and CD8+T cells and a higher resting CD4+T infiltration. Patients who had a low score had less abundance of PD-1, CTLA-4, and TIGI. The m6Ascore in three cohorts (GSE78220, TCGA-SKCM, and IMvigor210) failed to give a good prediction to estimate the patient’s response to immunotherapy. The role of m6Ascore to evaluate the effect of immunotherapy needs to be figured out with more research.
This research in the discussion by Wang et al. highlights the role of m6A in pancreatic cancer and opens up potential new research avenues. With more research, its use as a potential tool for the diagnosis of pancreatic cancer can be explored.
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Reference: Wang, L., Zhang, S., Li, H. et al. Quantification of m6A RNA methylation modulators pattern was a potential biomarker for prognosis and associated with tumor immune microenvironment of pancreatic adenocarcinoma. BMC Cancer 21, 876 (2021). https://doi.org/10.1186/s12885-021-08550-9
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Author info
Vaishnavi Kardale is a master’s student at the Bioinformatics Centre, Savitribai Phule University. She is interested in protein folding mechanisms and wants to study them further.
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