GRCh38 · COSMIC v98


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Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.
Paper ID
Aguiar TFM, Rivas MP, Costa S, Maschietto M, Rodrigues T, Sobral de Barros J, Barbosa AC, Valieris R, Fernandes GR, Bertola DR, Cypriano M, Caminada de Toledo SR, Major A, Tojal I, Apezzato MLP, Carraro DM, Rosenberg C, Lima da Costa CM, Cunha IW, Sarabia SF, Terrada DL and Krepischi ACV
International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil.
Frontiers in oncology, 2020;10:556
ISSN: 2234-943X
PMID: 32432034 (view at PubMed or Europe PMC)
Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated genes were detected: <i>CTNNB1</i> and two novel candidates, <i>CX3CL1</i> and <i>CEP164</i>. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the <i>CX3CL1</i> gene; evaluation of RNA and protein expression revealed upregulation of <i>CX3CL1</i> in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the <i>CX3CL1/CX3CR1</i> pathway occurs in hepatoblastomas. In inflammatory regions of hepatoblastomas, CX3CL1/CX3CR1 were not detected in the infiltrated lymphocytes, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative labeling in tumor cells, but strongly positive infiltrated lymphocytes. Altogether, these data suggested that <i>CX3CL1/CX3CR1</i> 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, mostly related to tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. Overall, we present here novel candidate genes for hepatoblastoma, with evidence that <i>CX3CL1/CX3CR1</i> chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures.
Paper Status