Genomic Predictors for Recurrence of Liver Cancer

Plos: In a new study,  Ju-Seog Lee and colleagues develop a genetic predictor that can identify patients at high risk for late recurrence of liver cancer (hepatocellular carcinoma, HCC) and provided new biomarkers for risk stratification.


Primary liver cancer (hepatocellular carcinoma)—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development.

Why Was This Study Done?

Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surgery, arises from the spread of primary cancer cells into the surrounding liver that left behind during surgery. Late recurrence, which typically happens more than two years after surgery, involves the development of completely new tumors and seems to be the result of chronic liver damage. Because early and late recurrence have different clinical courses, it would be useful to be able to predict which patients are at high risk of which type of recurrence. Given that injury, inflammation, and regeneration seem to prime the liver for HCC development, might the gene expression patterns associated with these conditions serve as predictive markers for the identification of patients at risk of late recurrence of HCC? Here, the researchers develop a genomic predictor for the late recurrence of HCC by examining gene expression patterns in tissue samples from livers that were undergoing injury and regeneration.

What Did the Researchers Do and Find?

By comparing gene expression data obtained from liver biopsies taken before and after liver transplantation or resection and recorded in the US National Center for Biotechnology Information Gene Expression Omnibus database, the researchers identified 233 genes whose expression in liver differed before and after liver injury (the hepatic injury and regeneration, or HIR, signature). Statistical analyses indicate that the expression of the HIR signature in archived tissue samples was significantly associated with late recurrence of HCC in three independent groups of patients, but not with early recurrence (a significant association between two variables is one that is unlikely to have arisen by chance). By contrast, a tumor-derived 65-gene signature previously developed by the researchers was significantly associated with early recurrence but not with late recurrence. Notably, as few as four genes from the HIR signature were sufficient to construct a reliable predictor for late recurrence of HCC. Finally, the researchers report that many of the genes in the HIR signature encode proteins involved in inflammation and cell death, but that others encode proteins involved in cellular growth and proliferation such as STAT3, a protein with a well-known role in liver regeneration.

What Do These Findings Mean?

These findings identify a gene expression signature that was significantly associated with late recurrence of HCC in three independent groups of patients. Because most of these patients were infected with HBV, the ability of the HIR signature to predict late occurrence of HCC may be limited to HBV-related HCC and may not be generalizable to HCC related to other causes. Moreover, the predictive ability of the HIR signature needs to be tested in a prospective study in which samples are taken and analyzed at baseline and patients are followed to see whether their HCC recurs; the current retrospective study analyzed stored tissue samples. Importantly, however, the HIR signature associated with late recurrence and the 65-gene signature associated with early recurrence provide new insights into the biological differences between late and early recurrence of HCC at the molecular level. Knowing about these differences may lead to new treatments for HCC and may help clinicians choose the most appropriate treatments for their patients.