Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients

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Marques Aguiar, Talita Ferreira ^{[1, 2]} ; Rivas, Maria Prates ^[2] ; Costa, Silvia ^[2] ; Maschietto, Mariana ^[3] ; Rodrigues, Tatiane ^[2] ; de Barros, Juliana Sobral ^[2] ; Barbosa, Anne Caroline ^[2] ; Valieris, Renan ^[1] ; Fernandes, Gustavo R. ^[4] ; Bertola, Debora R. ^[2] ; Cypriano, Monica ^[5] ; Caminada de Toledo, Silvia Regina ^[5] ; Major, Angela ^{[6, 7]} ; Tojal, Israel ^[1] ; de Pinho Apezzato, Maria Lucia ^[8] ; Carraro, Dirce Maria ^[1] ; Rosenberg, Carla ^[2] ; Lima da Costa, Cecilia Maria ^[9] ; Cunha, Isabela W. ^{[10, 11]} ; Sarabia, Stephen Frederick ^{[6, 7]} ; Terrada, Dolores-Lopez ^{[6, 12, 7, 13]} ; Victorino Krepischi, Ana Cristina ^[2]

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^[1] AC Camargo Canc Ctr, Int Ctr Res, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Genet & Evolutionary Biol, Inst Biosci, Human Genome & Stem Cell Res Ctr, Sao Paulo - Brazil

^[3] Boldrini Childrens Ctr, Campinas - Brazil

^[4] Univ Sao Paulo, Dept Biochem, Inst Chem, Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Pediat, Adolescent & Child Canc Support Grp GRAACC, Sao Paulo - Brazil

^[6] Baylor Coll Med, Houston, TX 77030 - USA

^[7] Texas Childrens Hosp, Dept Pathol & Immunol, Houston, TX 77030 - USA

^[8] AC Camargo Canc Ctr, Dept Pediat Oncol Surg, Sao Paulo - Brazil

^[9] AC Camargo Canc Ctr, Dept Pediat Oncol, Sao Paulo - Brazil

^[10] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo - Brazil

^[11] Rede Dor Sao Luiz, Dept Pathol, Sao Paulo - Brazil

^[12] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 - USA

^[13] Texas Childrens Canc Ctr, Dept Pediat, Houston, TX - USA

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN ONCOLOGY; v. 10, MAY 5 2020.
• Citações Web of Science: 0

Resumo

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: CTNNB1 and two novel candidates, CX3CL1 and CEP164. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed upregulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 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 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, 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 CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 18/05961-2 - Identificação variantes genéticas relacionadas à predisposição a câncer em coorte de pacientes com tumores embrionários e tumores pediátricos com sinais clínicos adicionais
• Beneficiário: Anne Caroline Barbosa Teixeira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/04785-0 - Estudo de mutações somáticas identificadas em sequenciamento de exoma de hepatoblastoma
• Beneficiário: Talita Ferreira Marques Aguiar
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 17/11212-0 - Estudos epigenômicos em hepatoblastomas
• Beneficiário: Talita Ferreira Marques Aguiar
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 16/23462-8 - Estudo de mecanismos epigenéticos em tumores de fígado: modulação da expressão de genes reguladores da epigenética e análise de expressão gênica por RNAseq em hepatoblastoma.
• Beneficiário: Maria Prates Rivas
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/21047-9 - Câncer na infância - predisposição genética e mecanismos de origem
• Beneficiário: Ana Cristina Victorino Krepischi
• Modalidade de apoio: Auxílio à Pesquisa - Regular