Identification of molecular subtypes based on histone arginine methylation in bladder cancer

Abstract

Abstract Background ​Histone arginine methylation is an important feature in bladder cancer that affects prognosis and therapeutic response. However, the investigation of molecular subtypes based upon histone arginine methylation is still being exploited. Methods From the TCGA database, we obtained the RNA sequencing and somatic mutation results of 412 bladder cancer patients. To identify molecular subtypes associated with histone arginine methylation, consensus clustering was performed. These histone arginine methylation-associated subtypes were compared in terms of prognosis, clinical features, immune cell infiltration, and somatic mutation profiles. Moreover, we utilized the CTRP and GDSC databases to examine how drug sensitivity is related to mRNA expression of HAM-related genes. Results Based on our findings, bladder cancer could be divided into histone arginine methylation-low (HAM-low) and histone arginine methylation-high (HAM-high) subtypes with distinctive clinicopathological characteristics, tumor microenvironment and prognostic. There is a dismal prognosis associated with high histone arginine methylation subtypes and a high frequency of oncogene mutations in these subtypes. Conversely, histone arginine methylation-low subtypes are associated with a better clinical outcome and a lower frequency of oncogene mutations. There was a correlation between the HAM-high subtype and the immune-hot phenotype, while the HAM-low subtype was associated with the immune-cold phenotype. As well, we develop and validate a prognostic model associated with histone arginine methylation that has good predictive power. The results of drug sensitivity tests revealed that HAM-related genes are associated with resistance to most drugs. A positive correlation was found between XAV939 or Cetuximab and HAM-related gene expression, suggesting that these agents may be beneficial to patients who fall into the HAM-high subgroup of BC patients. Conclusion ​In summary, we have established a novel bladder classification based on histone arginine methylation subtypes. This classification has significant consequences for the estimation of prognosis and drug sensitivity, as well as the tumor microenvironment.