Abstract PO010: Molecular characterization of pediatric hepatocellular carcinoma: genomic, methylomic and transcriptomic analysis
Authors: Carrillo-Reixach Juan , del Río-Álvarez Álvaro , Royo Laura , Domingo-Sàbat Montserrat , Alaggio Rita , de Krijger Ronald , Vokuhl Christian , Garrido Marta , Guerra Laura , Sábado Constantino , Hernández Francisco , López-Santamaría Manuel , Bajčiová Viera , Maibach Rudolf , Childs Margaret , Czauderna Piotr , Wheatley Keith , Kappler Roland , Cairo Stefano , Morland Bruce , Sala Margarita , Sarrias Maria Rosa , Armengol Carolina 
Published: September 2022

Background: The main pediatric liver tumors are hepatoblastoma (HB) and, to a lesser extent, pediatric hepatocellular carcinoma (HCC). HB appears at an early age (&lt;3 years) while HCC is diagnosed mainly in older children (&gt;8 years) or adolescents and it is usually associated to underlying metabolic diseases. HEM-NOS (Hepatocellular malignant neoplasm, not otherwise specified) is a recent entity with histopathological features of HB and HCC. Due to the rarity of the disease (&lt;1 case per million children), the biology of HCC and their similarity with HB has been poorly explored. Aims: To molecularly characterize pediatric HCC at the genomic, transcriptomic and epigenomic level and to perform a comparative study with HB and HEM-NOS. Methodology: We performed a genomic (Cytoscan, ThermoFisher), epigenomic (EPIC/850k, Illumina) and transcriptomic (HTA 2.0 array, ThermoFisher) studies on 8 HCC and compared them with already published omics data of 31 HB, 2 HEM-NOS and 19 control non-tumor liver (NT) samples (Carrillo-Reixach et al, J Hepatol, 2020). The results obtained were validated in an independent series of 19 HCC, including 10 fibrolamellar HCC (FL-HCC), 56 HB, 7 HEM-NOS and 5 NTs using QUAlu and Nanostring techniques for assessing DNA methylation and gene expression, respectively. Results: We identified CTNNB1 gene mutations in 73%, 50% and 14% of HB, HEM-NOS and HCC, respectively. Contrarily, TERT mutations were only found in HEM-NOS and HCC tumors. FL-HCC had the DNAJB1:PRKACA fusion transcript and in one case without this fusion, a deletion in the PRKCA gene was identified. The genome of HCC and HEM-NOS had higher number of chromosomal losses than HB. Moreover, HBs and HEM-NOS showed a higher DNA hypomethylation than HCC whereas HCC was characterized by CpG island hypermethylation. Two imprinting regions were differently expressed in 14q32 (DLK1/DIO3) and 15q11.2 (SNORD115/116) in HB and HCC, respectively. Finally, we identified the SPINK1 gene (Serine peptidase inhibitor, kazal type 1) as an overexpressed gene in HCC that was strongly associated with prognosis of patients with liver cancer in both training (Log-Rank=0.008) and validation sets (Log-rank=0.028). Using XENA database, we found also that different SPINK1 expression was also associated with adult HCC prognosis (n=357, Log-rank=0.017). Conclusions: The characterization of HCC and its comparison with HB allowed us to identify potential diagnostic and prognostic markers that could help to improve the clinical management of childhood liver cancer.

Citation Format: Juan Carrillo-Reixach, Álvaro del Río-Álvarez, Laura Royo, Montserrat Domingo-Sàbat, Rita Alaggio, Ronald de Krijger, Christian Vokuhl, Marta Garrido, Laura Guerra, Constantino Sábado, Francisco Hernández, Manuel López-Santamaría, Viera Bajčiová, Rudolf Maibach, Margaret Childs, Piotr Czauderna, Keith Wheatley, Roland Kappler, Stefano Cairo, Bruce Morland, Margarita Sala, Maria Rosa Sarrias, Carolina Armengol. Molecular characterization of pediatric hepatocellular carcinoma: genomic, methylomic and transcriptomic analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO010.