Genetic signature may lead to better treatments for pediatric liver cancers

Dec 8 2008

Scientists have identified a genetic signature that is remarkably effective at predicting the prognosis of an aggressive liver cancer in children.

The research, published by Cell Press in the December issue of the journal Cancer Cell, may lead to better treatments for pediatric liver cancers.

Hepatoblastoma (HB), the most common liver cancer in children, is associated with abnormal activation of the Wnt/?-catenin signaling pathway. Although the specific details are not clear, Wnt signaling is essential for normal liver development. HB tumors can be comprised of cells that resemble fetal cells or immature progenitor cells but the cellular make-up of the tumor is frequently heterogeneous, precluding its systematic use for guiding treatment or predicting outcome.

"At present, few studies have addressed whether intrinsic biological differences between tumors impact HB prognosis. Moreover, new treatments are urgently needed for advanced stage tumors, and better understanding of HB pathobiology is a prerequisite for developing targeted therapies," explains senior study author Dr. Marie-Annick Buendia from the Oncogenesis and Molecular Virology Unit at the Pasteur Institute and Inserm Unit in Paris, France.

Dr. Buendia and colleagues used a sophisticated genetic screening technique to investigate the pathogenesis of HB. They found that ?-catenin was linked with two distinct tumor subclasses that reflect early and late phases of prenatal liver development. Further, they discovered a specific genetic signature that was useful for identifying the two tumor subclasses and predicting disease outcome.

The researchers also demonstrated that the highly proliferating, early stage tumors had characteristics associated with stem cells. Activation of Myc, a stem cell marker that is commonly overexpressed in cancer, appeared to play a key role in this tumor subtype. Further, activation of Myc in mice induced tumors that were strikingly similar to the human immature subtype of HB and inhibition of Myc in HB cells impaired tumorigenesis.

"We demonstrate that hepatic differentiation stage and clinical behavior of HB are intimately linked, and we identify an expression signature with dual capacities in recognizing liver developmental stage and predicting disease outcome. These data can be applied to improve clinical management of pediatric liver cancer and develop therapeutic strategies," concludes Dr. Buendia.