Gene signature and prognostic merit of M6a regulators in colorectal cancer

Abstract

Although new diagnostic techniques and treatments are increasingly updated, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to evaluate gene signature and prognostic ability of N6-methyladenosine in CRC. We used the gene expression, copy number variation, simple nucleotide variation and clinical messages from The Cancer Genome Atlas database. We first identified mutation and copy number variations of N6-methyladenosine regulatory genes in both colon adenocarcinoma and rectum adenocarcinoma. Fourteen of all 17 N6-methyladenosine regulatory genes were related with higher mRNA expression, whereas deletion leads to reduced expression. Using univariate Cox regression analysis, RBM15, YTHDC2, and METTL14 genes in the rectum adenocarcinoma samples were conspicuously associated with the prognosis of patients. Based on the least absolute shrinkage and selection operator regression models, we built a 2-gene (YTHDC2 and IGF2BP3) signature of N6-methyladenosine regulators with prognostic ability. The 1-, 3-, and 5-year AUCs of this signature were all greater than 0.6, and the P-value for risk prediction for patients was also less than 0.0001. Moreover, high IGF2BP3 gene expression was significantly associated with IFN-γ in colon adenocarcinoma , and related to the azurophil granule membrane pathway in rectum adenocarcinoma. High YTHDC2 expression in colon adenocarcinoma is closely related to cell energy metabolism. In the rectum adenocarcinoma, high YTHDC2 gene expression is related to the cell centrosome pathway. In conclusion, for the first time, we identified genetic changes of N6-methyladenosine modulators and built a prognostic gene signature in CRC.

Impact statement

Although new diagnostic techniques and treatments are increasingly updated for CRC, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine (m6A) as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to identify gene signature and prognostic ability of m6A modulators in CRC. For the first time, we identified genetic changes of m6A modulators and built prognostic gene signature in CRC, which may provide effective targets for the diagnosis and management of CRC.