Lineage factor functions in renal carcinoma - ATAC-seq

The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1. Overall design: ATAC-seq profiling in experimental models of renal carcinoma.