NSD1 inactivation and SETD2 mutation drive a convergence toward loss-of-function of H3K36 writers in clear-cell renal cell carcinomas

Extensive dysregulation of chromatin-modifying genes in clear-cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the crosstalk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear-cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of vascular endothelial growth factor receptor genes (FLT4, FLT1 and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss-of-function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC.

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