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Gustavo W. Leone, Ph.D.

Gustavo Leone, Ph.D.

Director, Hollings Cancer Center
Senior Associate Dean, Oncology, College of Medicine
Department: Biochemistry & Molecular Biology
Programs: Inflammation, End Organ Disease


Research Interests:

The genomic landscape of hepatocellular carcinoma (HCC) differs from that of most other cancer types since it is void of dominant driving genetic alterations. Whole genome analysis of HCC has revealed a large number of “heterogeneous” mutations, each contributing a small portion of the entire patient population. Either through amplification of negative regulators, genetic or epigenetic inactivation of positive regulators, or mutations in RB1 itself, disruption of the RB pathway is believed to be a universal requirement for cancer development. However, there is a surprising paucity of genetic alterations in the main downstream transcriptional effectors of the RB pathway, the E2F transcription factors, which has cast doubt on their direct involvement in the genesis of cancer. Our recent mutational analyses identified E2F1 and E2F3 copy-number gains in human HCC patients and show in mouse models that these modest genetic alterations are sufficient to initiate HCC. Remarkably, spontaneous HCC developed in the absence of additional organ-specific cancer types or any significant impact on fetal to adult development. Using a series of E2F alleles to finely tune E2F transcriptional output, we show that increasing output by gains in E2f1 and E2f3b activators or loss of E2f7 and E2f8repressors, leads to HCC development in mice.

Consistent with broad genomic mutation landscape of hepatocellular carcinoma, we recently showed that not all HCC patients suffer E2F1 and/or E2F3 copy number gains or E2F7 and E2F8 losses, but surprisingly, virtually all tumor samples analyzed exhibit increased expression of E2F1/E2F3B target genes. We hypothesize that dysregulation of the E2F transcriptional program is sufficient to drive HCC development in mice and is likely a downstream and necessary consequence of most if not all genetic alterations associated with HCC development.


PubMed Collection