PR/SET Domain Family and Cancer: Novel Insights from The Cancer Genome Atlas

Abstract

The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein⁻protein, protein⁻RNA, or protein⁻DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of <i>PRDM</i> genes, we reanalyzed the Exome- and RNA-Seq public datasets available at The Cancer Genome Atlas portal. Overall, <i>PRDM2</i>, <i>PRDM3/MECOM</i>, <i>PRDM9</i>, <i>PRDM16</i> and <i>ZFPM2/FOG2</i> were the most mutated genes with pan-cancer frequencies of protein-affecting mutations higher than 1%. Moreover, we observed heterogeneity in the mutation frequencies of these genes across tumors, with cancer types also reaching a value of about 20% of mutated samples for a specific <i>PRDM</i> gene. Of note, <i>ZFPM1/FOG1</i> mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region. These findings, together with OncodriveCLUST results, suggest it could be putatively considered a cancer driver gene in this malignancy. Finally, transcriptome analysis from RNA-Seq data of paired samples revealed that transcription of <i>PRDMs</i> was significantly altered in several tumors. Specifically, <i>PRDM12</i> and <i>PRDM13</i> were largely overexpressed in many cancers whereas <i>PRDM16</i> and <i>ZFPM2/FOG2</i> were often downregulated. Some of these findings were also confirmed by real-time-PCR on primary tumors.