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Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway

Talita Ferreira Marques Aguiar, Maria Prates Rivas, Silvia Costa, Tatiane Rodrigues, Juliana Sobral de Barros, Anne Caroline Barbosa, Mariana Maschietto, Renan Valieris, Gustavo Ribeiro Fernandes, Monica Cypriano, Silvia Regina Caminada de Toledo, Angela Major, Israel Tojal, Maria Lúcia de Pinho Apezzato, Dirce Maria Carraro, Carla Rosenberg, Cecilia Maria Lima da Costa, Isabela Werneck da Cunha, Stephen Frederick Sarabia, Dolores-López Terrada, Ana Cristina Victorino Krepischi
doi: https://doi.org/10.1101/555466
Talita Ferreira Marques Aguiar
aInternational Center for Research, A. C. Camargo Cancer Center, São Paulo, BR
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Maria Prates Rivas
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Silvia Costa
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Tatiane Rodrigues
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Juliana Sobral de Barros
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Anne Caroline Barbosa
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Mariana Maschietto
cBoldrini Children’s Center, Campinas, BR
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Renan Valieris
aInternational Center for Research, A. C. Camargo Cancer Center, São Paulo, BR
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Gustavo Ribeiro Fernandes
dDepartment of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, BR
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Monica Cypriano
eDepartment of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, BR
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Silvia Regina Caminada de Toledo
eDepartment of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, BR
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Angela Major
fDepartment of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, USA
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Israel Tojal
aInternational Center for Research, A. C. Camargo Cancer Center, São Paulo, BR
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Maria Lúcia de Pinho Apezzato
gDepartment of Pediatric Oncological Surgery, A. C. Camargo Cancer Center, São Paulo, BR
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Dirce Maria Carraro
aInternational Center for Research, A. C. Camargo Cancer Center, São Paulo, BR
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Carla Rosenberg
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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Cecilia Maria Lima da Costa
hDepartment of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, BR
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Isabela Werneck da Cunha
iDepartment of Pathology, Rede D’OR-São Luiz, São Paulo, BR
jDepartment of Pathology, A. C. Camargo Cancer Center, São Paulo, BR
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Stephen Frederick Sarabia
fDepartment of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, USA
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Dolores-López Terrada
fDepartment of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, USA
kTexas Children’s Cancer Center, Department of Pediatrics, Houston, USA
lDan L. Duncan Cancer Center, Baylor College of Medicine, Houston, USA
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Ana Cristina Victorino Krepischi
bHuman Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BR
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  • For correspondence: ana.krepischi@ib.usp.br
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ABSTRACT

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>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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 22, 2019.
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Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway
Talita Ferreira Marques Aguiar, Maria Prates Rivas, Silvia Costa, Tatiane Rodrigues, Juliana Sobral de Barros, Anne Caroline Barbosa, Mariana Maschietto, Renan Valieris, Gustavo Ribeiro Fernandes, Monica Cypriano, Silvia Regina Caminada de Toledo, Angela Major, Israel Tojal, Maria Lúcia de Pinho Apezzato, Dirce Maria Carraro, Carla Rosenberg, Cecilia Maria Lima da Costa, Isabela Werneck da Cunha, Stephen Frederick Sarabia, Dolores-López Terrada, Ana Cristina Victorino Krepischi
bioRxiv 555466; doi: https://doi.org/10.1101/555466
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Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway
Talita Ferreira Marques Aguiar, Maria Prates Rivas, Silvia Costa, Tatiane Rodrigues, Juliana Sobral de Barros, Anne Caroline Barbosa, Mariana Maschietto, Renan Valieris, Gustavo Ribeiro Fernandes, Monica Cypriano, Silvia Regina Caminada de Toledo, Angela Major, Israel Tojal, Maria Lúcia de Pinho Apezzato, Dirce Maria Carraro, Carla Rosenberg, Cecilia Maria Lima da Costa, Isabela Werneck da Cunha, Stephen Frederick Sarabia, Dolores-López Terrada, Ana Cristina Victorino Krepischi
bioRxiv 555466; doi: https://doi.org/10.1101/555466

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