<i>NSD1</i> Inactivation and <i>SETD2</i> Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas.

Abstract

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 cross-talk 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 VEGF genes (<i>FLT4, FLT1</i>, and <i>KDR</i>). 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 <i>NSD1</i> as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring <i>NSD1</i> methylation were of higher grade and stage in different ccRCC datasets. <i>NSD1</i> promoter methylation correlated with <i>SETD2</i> somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of <i>NSD1</i> displayed a specific genome-wide methylome signature consistent with the <i>NSD1</i> 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. <i>Cancer Res; 77(18); 4835-45. ©2017 AACR</i>.