7P - Association study between genetic variants in regulatory gene for RNA modification and prognosis in non-small cell lung cancer

Background

RNA modifications play an important role in gene expression and cellular functions. Regulatory genes for RNA modifications, such as methyltransferase 1, tRNA methylguanosine (METTL1) and adenosine deaminase RNA specific B1 (ADAR2), have been correlated with cancer progression due to their effects on mRNA and tRNA editing.

Methods

In this study, the association between polymorphisms in 25 RNA modification regulatory genes and the prognosis of 744 non-small cell lung cancer (NSCLC) patients was evaluated. Among the 21 single nucleotide polymorphisms (SNPs) studied, three were significantly associated with the overall survival (OS) of patients.

Results

The SNP rs10877013T>C in METTL1 gene was significantly associated with better OS (under a dominant model, adjusted hazard ratio [aHR] = 0.67, 95% confidence interval [CI] = 0.48-0.93, P = 0.02). METTL1 rs10877013 is located in intronic region, so rs703842G>A located in METTL13′untranslated region (3′UTR) with a strong LD (D′ = 1.0 and r² ≥ 0.9) was found. The SNPs rs3788152A>C and rs414743G>A in the ADAR2 gene were associated with significantly worse OS (under a dominant model, aHR = 1.46, 95% CI = 1.05-2.03, P = 0.03; under a codominant model, aHR = 1.40, 95% CI = 1.02-1.93, P = 0.04, respectively). A dual luciferase assay showed a significantly higher promoter activity of METTL1 with the rs703842 A allele than with the G allele in H1299 (P = 6.5×10^-6) and H1703 lung cancer cells (P = 0.03). Knockdown of METTL1 with specific siRNA induced cell apoptosis and decreased cell proliferation, invasion, and migration in lung cancer cells.

Conclusions

In conclusion, the investigation reveals that genetic variations METTL1 rs10877013T>C, ADAR2 rs3788152A>C, and ADAR2 rs414743G>A polymorphisms within RNA modification regulatory genes are associated with survival outcomes of NSCLC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.