An international study of childhood liver cancer led by the IGTP provides new clues about its biology to improve clinical management of the disease
The Childhood Liver Oncology Research Group (C-Log) led by Carolina Armengol has published results in the context of the European project ChiLTERN which aims to improve the clinical treatment of paediatric hepatoblastoma (HB), a rare disease that mostly affects children under three. The results have been published in the Journal of Hepatology
The study describes the epigenetic fingerprint of these tumours for the first time; this can be used to diagnose patients more accurately. Based on the epigenetic characteristics the group has proposed a new molecular tool called Molecular Risk Stratification of Hepatoblastoma (MRS-HB), which will complement the current clinical tools. The use of this tool, together with clinical data will allow doctors to stratify patients better according to their prognostic, so taking another step towards precision medicine. Additionally, the researchers have also discovered a promising new therapeutic target for the disease. All these discoveries are being validated within the ChiLTERN Project and the cohort of patients registered in its international clinical trial, (PHITT, NCT03017326), the first for this type of tumour.
The patients who recover from the disease can have secondary effects for a long time due to the chemotherapy and there are no alternative treatments for those who are resistant to those on offer. "Even though not all cases have a bad prognosis, it is a devastating disease for patients and families, so the improvement of the molecular knowledge of this rare cancer is essential for the discovery of new therapies," explains Juan Carrillo-Reixach, one of the leading researchers on the study.
"These results show how important it is to integrate molecular information to improve the diagnosis and apply the best treatment in each case," adds Carrillo-Reixach. Using all this information together with clinical data the doctors can be more accurate in diagnosing each patient and recommend the best treatment available in each case.
There are only 1.8 cases of childhood liver cancer for every million children per year, which means it is considered a rare disease and it is very difficult to study as there are very few cases and they are all in different places. "Our group is working to get over these difficulties and provide answers for doctors treating the disease," explains Càrol Armengol, who designed and led the study. "Our results show for the first time that epigenetics is important in hepatoblastoma and we have identified new therapies which have been shown to be effective in human tumours in a mouse model," she adds. This work includes a great number of samples and has been possible thanks to the establishment of a stable network of researchers from the leading European paediatric hospitals, with the support of the Spanish Society of Paediatric Hematology and Oncology (SEHOP) and of SIOPEL, the International Childhood Liver Tumors Strategy Group.
The group at the IGTP is funded by the Catalan and Spanish Governments, as well as by the European projects ChiLTERN and iPC, both within the Horizon 2020 Programme of the European Union (Grant agreements 668596 i 826121). "This type of project is only possible when there is serious investment in research combined with well-coordinated international networks," states Armengol.
New Genes and artificial intelligence to study them in depth
It is known that hepatoblastoma is a type of tumour that has very few mutations. Using a series of high technology techniques the group has found a series of epigenetic characteristics that constitute chemical markers on the genetic material that can change the behaviour of cancer cells in this childhood cancer.
By first studying a gene with anti-tumour functions (BLCAP) the researchers found alterations in the RNA sequence, but not in the DNA, a mechanism known as editing. Next they identified a small region of the genome on chromosome 14, which is found to be highly altered in cancer samples in comparison with samples of healthy liver tissue. "The most important thing is that this region contains genes that are known to be implicated in the development of liver cancer," points our Armengol.
With further studies concentrating on epigenetic marks (methylation) the researchers have been able to identify different groups of tumours that resembled various different stages of liver development. To test the use of these findings for patients the researchers have compared epigenetic information from tumours with the clinical data of the same patients and have found that the molecular information is associated with different prognoses. Furthermore, they have divided the patients into prognostic groups with low, medium or high risk, depending on the number of epigenetic biomarkers found in their samples. A posterior statistical analysis has demonstrated that the clinical diagnosis and the molecular diagnosis are independent in a way that they can be used together and will provide more complete information to doctors.
A global analysis has found another gene (CHKA), which is one of those that are more highly expressed in medium and high risk tumours. In the laboratory researchers have implanted fragments of patient's tumours in mice and have shown that it is possible to inhibit this gene and stop cell growth, reducing the size of the tumour. More studies must be undertaken to test this new finding as a possible therapeutic option in this type of cancer.
"The main limitation of this study is that the samples come from patients who have already received chemotherapy," highlights Armengol. "Our objective now is to validate these discoveries with samples from before and after treatment obtained from patients included in the international PHITT trial, which is underway. We are also analysing all the molecular data we have generated during this study in more depth using artificial intelligence tools thanks to the participation of our group in the iPC Project. With all these projects in progress, our objective is to show the value of molecular data in the clinical management of these patients. This in turn, will in the future improve their survival rate and the quality of life of patients who have this type of cancer."
Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications
Carillo-Reixach et al. Journal of Hepatology, Volume 73, Issue 2, August 2020, Pages 328-341, doi.org/10.1016/j.jhep.2020.03.025
This project has received funding from the Instituto de Salud Carlos III, ISCIII (PI09/00751, PI10/02082, PI13/02340) and from the European Union's Horizon 2020 research and innovation programme under grant agreements No 668596 (ChiLTERN) and No 826121 (iPC). Carolina Armengol and Maria Rosa Sarrias were supported by Ramón y Cajal (RYC-2010-07249) and Miguel Servet (CPII14/00021) programs of the Ministry of of Science and Innovation and ISCIII, respectively. They and Marina Simon received funding from CIBERehd (CB06/04/0033) ). They and Juan Carrillo-Reixach is supported by the Catalan Agency for Management of University and Research Grants (AGAUR, 2019 FI_B 01024; 2017-SGR-490). The IGTP is a member of the CERCA network of institutes.