The progress in this area was marked with sequencing of the human genome in 2001 which allowed us to interrogate the entire human genome for genetic associations, both within genes and between genes. As a follow-up to that, we were able to identify, because of the known biology of other genetic changes that respond to targeted approaches, that a targeted approach would be appropriate rather than asking what genetic changes occur in the genome associated with hepatocellular carcinoma. We askedwhether the genetic changes associated with fundamental mechanisms such as HBV-induced fibrosis, vesicle trafficking and cytokine signaling are associated with HBV-related HCC? These results clearly indicate that some of those processes and some of those genetic changes are involved.

　　We are still most concerned about hepatitis B and C, but the unknown population is fatty liver disease where we think there will be a rising incidence of cancer in patients who are obese and have non-alcoholic steatohepatitis. So currently, we still worry most about viral hepatitis patients but this extends to patients with other diseases including fatty liver as a consequence of NASH but also alcohol.

　　We know that fibrosis predisposes to liver cancer and we are only beginning to understand the mechanisms linking fibrosis mechanistically, but there are many potential associations which include the stromal microenvironment, the immune environment, the mechanical features of the tissue and particularly tissue stiffness, as well as changes in hepatic stellate cell gene expression that foster a microenvironment that is permissive for cancer. As you know from your own work, that can include innate immune signaling as well as genes that have not previously been linked to fibrosis pathogenesis.