E2F target score is associated with cell proliferation and survival of patients with hepatocellular carcinoma

Background: E2F target genes are essential for the cell cycle. A score that quantifies its activity is ex-pected to reflect the aggressiveness and prognosis of hepatocellular carcinoma. Methods: Cohorts of hepatocellular carcinoma patients (total n 1/4 655) from The Cancer Genome Atlas, GSE89377, GSE76427, and GSE6764 were analyzed. The cohorts were divided into high versus low by the median. Results: All the Hallmark cell proliferation-related gene sets were consistently enriched in hepatocellular carcinoma with high E2F targets score, and E2F score was associated with grade, tumor size, American Joint Committee on Cancer staging, proliferation score, and MKI67 expression, as well as with less abundance of hepatocytes and stromal cells. E2F targets enriched DNA repair, mTORC1 signaling, glycolysis, and unfolded protein response gene sets and were significantly associated with the higher intratumoral genomic heterogeneity, homologous recombination deficiency, and progression of hepa-tocellular carcinoma. On the other hand, there was no relationship between E2F targets and mutation rates or neoantigens. High E2F hepatocellular carcinoma did not enrich any of the immune-response-related gene sets but was associated with high infiltration of Th1, Th2 cells, and M2 macrophage; however, there was no difference in cytolytic activity. In both early (I and II) and late (III and IV) stages of hepatocellular carcinoma, a high E2F score was associated with worse survival and was an independent prognostic factor for overall and disease-specific survival in patients with hepatocellular carcinoma. Conclusion: The E2F target score, associated with cancer aggressiveness and worse survival, could be used as a prognostic biomarker in patients with hepatocellular carcinoma.& COPY; 2023 Elsevier Inc. All rights reserved.

Automated summary

This study found that the E2F target score, reflecting the activity of E2F target genes, is associated with the aggressiveness and prognosis of hepatocellular carcinoma. High E2F target score is associated with tumor grade, size, staging, proliferation score, MKI67 expression, as well as reduced abundance of hepatocytes and stromal cells. It is also associated with higher intratumoral genomic heterogeneity, homologous recombination deficiency, and progression of hepatocellular carcinoma.