PT - JOURNAL ARTICLE AU - Talita Ferreira Marques Aguiar AU - Maria Prates Rivas AU - Silvia Costa AU - Tatiane Rodrigues AU - Juliana Sobral de Barros AU - Anne Caroline Barbosa AU - Mariana Maschietto AU - Renan Valieris AU - Gustavo Ribeiro Fernandes AU - Monica Cypriano AU - Silvia Regina Caminada de Toledo AU - Angela Major AU - Israel Tojal AU - Maria Lúcia de Pinho Apezzato AU - Dirce Maria Carraro AU - Carla Rosenberg AU - Cecilia Maria Lima da Costa AU - Isabela Werneck da Cunha AU - Stephen Frederick Sarabia AU - Dolores-López Terrada AU - Ana Cristina Victorino Krepischi TI - Mutational burden of hepatoblastomas: a role for the <em>CX3CL1/CX3CR1</em> chemokine signaling pathway AID - 10.1101/555466 DP - 2019 Jan 01 TA - bioRxiv PG - 555466 4099 - http://biorxiv.org/content/early/2019/02/22/555466.short 4100 - http://biorxiv.org/content/early/2019/02/22/555466.full AB - Background Hepatoblastoma is an embryonal liver tumor supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. CTNNB1 is the only recurrently mutated gene, and this relative paucity of somatic mutations poses a challenge to risk stratification and development of targeted therapies.Methods In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case.Results Our data disclosed a low mutational background with only three recurrently mutated genes: CTNNB1 and two novel candidates, CX3CL1 and CEP164. The major finding was a recurrent mutation (A235G) identified in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed up-regulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas, with a predominance of these proteins in the cytoplasm of tumor cells. These proteins were not detected in the infiltrated lymphocytes of inflammatory regions of the tumors, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative tumor cells, but strongly positive infiltrated lymphocytes. Our data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, related only with tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C&gt;A mutations.Conclusions Overall, we present here evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with hepatoblastoma tumorigenesis or progression, besides reporting a novel mutational signature specific to a hepatoblastoma subset.