RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer

Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas

“…A recent study showed that SETD2 deficiency in ccRCC may represent an attractive therapeutic vulnerability for DNA hypomethylating agents (HMAs), and further provided preclinical and in vivo evidence that SETD2 -deficient tumors were extremely sensitive to combination treatment of HMAs and ICI. 41 Therefore, our convergent findings of PRC2 hypermethylation, EZH2 overexpression, and BAP1 and SETD2 loss provide valuable insights into the interplay between epigenetic alterations, immune modulation, and therapeutic implications in ccRCC patients who showed primary resistance to ICI treatment.…”

SETD2 loss in renal epithelial cells drives epithelial‐to‐mesenchymal transition in a TGF‐β‐independent manner

“…To investigate the extent to which our SETD2 isogenic model reflects SETD2 loss in primary human ccRCC tissue, we utilized the TCGA KIRC database for gene expression profiles. Given both the marked ITH known to occur in ccRCC [ 8 ] and the moderately frequent SETD2‐mutation‐independent loss of H3K36me3 and SETD2 downregulation [ 3 , 37 ], we curated a ‘high confidence’ set of primary ccRCC with intact SETD2 (no SETD2 mutation with high expression) to compare with SETD2‐deficient ccRCC (biallelic SETD2 inactivation accompanied by reduced expression; 12 ccRCCs from each group (Table S3 )). This is an especially important distinction as TCGA does not have H3K36me3 status available, so controlling for the expression status of the writer of H3K36me3 (SETD2) is essential for accurately comparing SETD2‐proficient to SETD2‐deficient tumors [ 37 ].…”

“…Given both the marked ITH known to occur in ccRCC [ 8 ] and the moderately frequent SETD2‐mutation‐independent loss of H3K36me3 and SETD2 downregulation [ 3 , 37 ], we curated a ‘high confidence’ set of primary ccRCC with intact SETD2 (no SETD2 mutation with high expression) to compare with SETD2‐deficient ccRCC (biallelic SETD2 inactivation accompanied by reduced expression; 12 ccRCCs from each group (Table S3 )). This is an especially important distinction as TCGA does not have H3K36me3 status available, so controlling for the expression status of the writer of H3K36me3 (SETD2) is essential for accurately comparing SETD2‐proficient to SETD2‐deficient tumors [ 37 ]. Using RNA‐seq data for these 24 samples, we performed principal component analysis in an unsupervised approach, revealing that SETD2 wild‐type and SETD2 mutant/low tumors largely segregate, and that 1702 genes are differentially expressed between these groups, indicating that SETD2 loss drives a distinct transcriptional signature in primary ccRCC as well (Fig.…”

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

“…In the SETD2-knockdown tumor model, increased CD8 + T cell infiltration and fewer MDSC following combined treatment with DAC and anti-PD-L1. ccRCC with altered SETD2 gene provides preclinical support for a therapeutic target for DAC and anti-PD-L1 ( 57 ). A case report about advanced HCC showed that immunotherapy could be effective, leading to long-term survival, and they focused on two mutated genes, SETD2 and LRP1B , to further explore ( 115 ).…”

“…SETD2 -deficient ccRCC is susceptible to mis-splicing. Gene set enrichment analysis (GSEA) shows that SETD2 -deficient negatively enriched the gene related to the mRNA splicing pathway ( 57 ). A genome-wide transcript profile for SETD2 -deficient primary ccRCC tumors demonstrated that altered splicing patterns or splicing defects, including intron retention and variation in exon utilization, are widely present in SETD2 -deficient cancers.…”