Molecular signatures of aggressive pediatric liver cancer

Liver masses account for 5 to 6% of pediatric cancer, which includes hepatoblastoma (HBL) along with rare cases of hepatocellular carcinoma (HCC). The most dangerous form of pediatric liver cancer is aggressive HBL, which can be characterized by chemo-resistance and multiple nodules or metastases at diagnosis, all correlating with worse clinical prognosis. Despite intensive studies and a significant improvement in overall outcomes, very little is known about the key molecular pathways which determine the aggressiveness of pediatric liver cancer. Although genetic mutations have been reported in aggressive HBL, they represent a low level (1.9% per case) and are found mainly in two genes CTNNB1 and NRF2. Over the past 5 years, our liver biology and tumor group at Cincinnati Children's Hospital Medical Center has investigated molecular signatures of aggressive HBL by examination of fresh tissue specimens, which were studied immediately after surgery to preserve the integrity of key biochemical pathways. Summarization of these high quality HBL samples discovered several critical pathways that are specific for aggressive pediatric liver cancer. These pathways include three characteristics: Conversion of tumor suppressor proteins (TSPs) by posttranslational modifications into oncogenesActivation of specific chromosomal regions, i.e., Aggressive Liver Cancer Domains (ALCDs) within many oncogenes, resulting in increased expression of oncogenesPotential epigenetic mechanisms that open chromatin structure of oncogenes via ALCDs. This commentary summarizes our key findings and discusses development of potential ALCD-based therapeutic approaches.