Further dissection of transcriptional profiling datasets from human and mouse HCCs harboring known gene alterations using gene set enrichment analysis (GSEA) revealed that human tumors with CDKN2A deletions transcriptionally resembled both mouse and human HCC harboring KMT2C alterations (Figure 3B and C) but not those harboring RB1 loss (Figure 3—figure supplement 2B), even though the tumor suppressor RB1 is regulated by CDKN2A/p16INK4A and their genomic alterations exhibit mutual exclusivity in multiple cancer types (Knudsen et al., 2020). This evidence concerns the gene RB1 and hepatocellular carcinoma.