Renal Medullary Carcinomas Harbor a Distinct Methylation Phenotype and Display Aberrant Methylation of Genes Related to Early Nephrogenesis

Abstract

Renal medullary carcinomas (RMC) are rare aggressive tumors of the kidneys, characterized by a loss of SMARCB1. Characteristically, these tumors arise in patients with sickle cell trait or other hemoglobinopathies. Recent characterization efforts have unraveled oncogenic pathways that drive tumorigenesis. Among these, gene sets that characterize replicative stress and the innate immune response are upregulated in RMCs. Despite comprehensive genetic and transcriptomic characterizations, commonalities or differences to other SMARCB1 deficient entities so far have not been investigated. We analyzed the methylome of seven primary RMC and compared it to other SMARCB1 deficient entities such as rhabdoid tumors (RT) and epithelioid sarcomas using 850 K methylation arrays. Moreover, we evaluated the differential gene expression of RMC using RNA-sequencing in comparison to other rhabdoid tumors. In accordance with previous gene expression data, we found that RMCs separate from other SMARCB1 deficient entities, pointing to a potentially different cell of origin and a role of additional genetic aberrations that may drive tumorigenesis and thus alter the methylome when compared to rhabdoid tumors. In a focused analysis of genes that are important for nephrogenesis, we particularly detected genes that govern early nephrogenesis such as FOXI1 to be hypomethylated and expressed at high levels in RMC. Overall, our analyses underscore the fact that RMCs represent a separate entity with limited similarities to rhabdoid tumors, warranting specific treatment tailored to the aggressiveness of the disease.