The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

Abstract

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.

TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway

“…There were 745,500 deaths in 2012 and 782,500 new cases are diagnosed globally, and China alone accounts for over 50% of the total cases [1,2]. Hepatocellular carcinoma (HCC) is the most common liver cancer and approximately 90% of primary liver cancer [3]. In addition, HCC is one of the most lethal malignancies due to its complexities, high metastasis and recurrence and limited treatment options [4].…”

A pipeline to create predictive functional networks: application to the tumor progression of hepatocellular carcinoma

“…The complexity of molecular events implicated in hepatocellular carcinoma progression is directly associated with its various etiologies that differently contribute to tumor initiation, growth and evasion. During last decades, multiscale omics data analysis of genome and proteome allowed to explore molecular networks associated with HCC and mathematical models have been developed namely to predict cancer [4] Id: M5890, available at http://software.broadinstitute.org/gsea/msigdb/geneset_page.jsp? geneSetName=HALLMARK_TNFA_SIGNALING_VIA_NFKB cell behavior [34].…”

“…For that purpose, we take advantage of the NFκB-dependent signature available in MSigDB [22,30]. We selected the HALLMARK TNFA SIGNALING VIA NFKB [4] signature which contains 200 genes regulated by NFκB in response to TNF. As shown in Additional file 1: Figure S7A, we demonstrated that these genes were more expressed in high aggressive HCC when compared with low aggressive ones supporting the activation of NFκB signaling.…”

Current strategies of precision medicine on advanced liver cancer

“…Studies show that the genetic and epigenetic changes of several critical genes were associated with the development of liver cancer. 31,32 The telomerase reverse transcriptase (TERT) gene promoter mutation is a common somatic genetic variant in HCC, which is present in 50% of HCC patients. 33 Telomere reverse transcriptase is an enzyme that is necessary for telomere elongation and preventing cell damage.…”

“…ARDI1A mutation reduces the transcription of tumor suppressor genes and increases the risk of HCC. 31,32 Studies showed that loss function of ARDI1A gene is associated with the development of many cancers such as kidney cancer, liver cancer and breast cancer. Further analysis also showed that ARDI1A gene mutation was located at the opposite stand of the genome to that of TP53 gene mutation, indicating that both ARDI1A and TP53 may jointly inhibit tumor formation.…”