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Study of somatic mutations identified in exome sequencing of hepatoblastoma

Grant number: 16/04785-0
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2016
Effective date (End): November 30, 2018
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Ana Cristina Victorino Krepischi
Grantee:Talita Ferreira Marques Aguiar
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Associated scholarship(s):17/11212-0 - Epigenomic studies in hepatoblastoma, BE.EP.DD

Abstract

Hepatoblastomas (HB) are embryonal tumors of the liver presenting with histological features that resemble the differentiation stages of hepatic cells. Molecular data on HB carcinogenesis is still scarce because of its rarity. The identification of the molecular pathways involved in the origin of HBs can expand the understanding of the connections between disruption of differentiation and cancer. We have the hypothesis that recurrent mutations in hepatoblastomas can occur, thus driving the carcinogenesis in addition to other mechanisms. To disclose rare somatic mutations, we performed a whole-exome sequencing of 6 HBs and their paired non-tumoral adjacent liver samples (capture method 244K Agilent SureSelect Target Enrichment; sequencing in Illumina HiSeq2000). Rare somatic variants (non-synonimous) were validated using target sequencing (capture method SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing Library, and Illumina MiSeq Multiplexed Sequencing Platform). An additional step of biological validation was performed using an independent cohort of 13 hepatoblastomas samples. Bioinformatic analysis of the exome data resulted in the identification of a total of 76 rare somatic variants mapped in coding sequences, and 46 of them have been validated in the target sequencing. The analysis detected four different pathogenic mutations in the CTNNB1 gene, in 4 tumors. The protein expression of beta-catenin was evaluated in 8 of the studied HBs, as well as in tissue-microarray consisting of 30 hepatoblastomas; the findings corroborated the activation of the Wnt, showing in most HBs the translocation of the protein beta-catenin to the nucleus in tumors in which CTNNB1 mutations were detected. Additionally, it was validated a recurrent somatic mutation affecting the exon 3 of the CX3CL1 in two HBs. Therefore, this gene has become an important candidate for this type of tumor and is currently under investigation. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VILLELA, DARINE; DE BARROS, JULIANA SOBRAL; DA COSTA, SILVIA SOUZA; AGUIAR, TALITA F. M.; CAMPAGNARI, FRANCINE; VIANNA-MORGANTE, ANGELA M.; KREPISCHI, ANA C. V.; ROSENBERG, CARLA. Detection of mosaicism for segmental and whole chromosome imbalances by targeted sequencing. ANNALS OF HUMAN GENETICS, v. 85, n. 1 AUG 2020. Web of Science Citations: 0.
MARQUES AGUIAR, TALITA FERREIRA; RIVAS, MARIA PRATES; COSTA, SILVIA; MASCHIETTO, MARIANA; RODRIGUES, TATIANE; DE BARROS, JULIANA SOBRAL; BARBOSA, ANNE CAROLINE; VALIERIS, RENAN; FERNANDES, GUSTAVO R.; BERTOLA, DEBORA R.; CYPRIANO, MONICA; CAMINADA DE TOLEDO, SILVIA REGINA; MAJOR, ANGELA; TOJAL, ISRAEL; DE PINHO APEZZATO, MARIA LUCIA; CARRARO, DIRCE MARIA; ROSENBERG, CARLA; LIMA DA COSTA, CECILIA MARIA; CUNHA, ISABELA W.; SARABIA, STEPHEN FREDERICK; TERRADA, DOLORES-LOPEZ; VICTORINO KREPISCHI, ANA CRISTINA. Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients. FRONTIERS IN ONCOLOGY, v. 10, MAY 5 2020. Web of Science Citations: 0.
RIVAS, MARIA PRATES; MARQUES AGUIAR, TALITA FERREIRA; FERNANDES, GUSTAVO RIBEIRO; CAIRES, LUIZ CARLOS; GOULART, ERNESTO; TELLES-SILVA, KAYQUE ALVES; CYPRIANO, MONICA; CAMINADA DE TOLEDO, SILVIA REGINA; ROSENBERG, CARLA; CARRARO, DIRCE MARIA; LIMA DA COSTA, CECILIA MARIA; DA CUNHA, ISABELA WERNECK; VICTORINO KREPISCHI, ANA CRISTINA. TET Upregulation Leads to 5-Hydroxymethylation Enrichment in Hepatoblastoma. FRONTIERS IN GENETICS, v. 10, JUN 12 2019. Web of Science Citations: 1.
MASCHIETTO, MARIANA; RODRIGUES, TATIANE CRISTINA; KASHIWABARA, ANDRE YOSHIAKI; SOUZA DE ARAUJO, ERICA SARA; MARQUES AGUIAR, TALITA FERREIRA; LIMA DA COSTA, CECILIA MARIA; DA CUNHA, ISABELA WERNECK; VASQUES, LUCIANA DOS REIS; CYPRIANO, MONICA; BRENTANI, HELENA; CAMINADA DE TOLEDO, SILVIA REGINA; PEARSON, PETER LEES; CARRARO, DIRCE MARIA; ROSENBERG, CARLA; KREPISCHI, ANA C. V. DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations. ONCOTARGET, v. 8, n. 58, p. 97871-97889, NOV 17 2017. Web of Science Citations: 2.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.