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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.

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