Study of somatic mutations identified in exome sequencing of hepatoblastoma

• Grant number: 16/04785-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2016
• End date: November 30, 2018
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ana Cristina Victorino Krepischi
• Grantee: Talita Ferreira Marques Aguiar
• Host 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)

Scientific publications

(7)

(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)

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; et al. TET Upregulation Leads to 5-Hydroxymethylation Enrichment in Hepatoblastoma. FRONTIERS IN GENETICS, v. 10, JUN 12 2019. (16/23462-8, 17/16283-2, 16/04785-0, 15/14821-1, 13/08028-1)

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. (16/04785-0, 13/08028-1, 14/17132-0)

AGUIAR, TALITA F.; RODRIGUES, TATIANE; PRATES, MARIA; DOS SANTOS, FERNANDA APARECIDA; FERNANDES, GUSTAVO; LIMA DA COSTA, CECILIA MARIA; DA CUNHA, ISABELA WERNECK; CYPRIANO, MONICA; CAMINADA DE TOLEDO, SILVIA REGINA; DE SOUZA, JORGE ESTEFANO S.; et al. Genomic studies of Brazilian patients with hepatoblastoma: Insight into somatic mutations using whole-exome sequencing. Cancer Research, v. 78, n. 13, p. 3-pg., 2018-07-01. (13/08028-1, 16/04785-0, 17/11212-0)

AGUIAR, T.; RODRIGUES, T.; DOS SANTOS, F. A.; SOBRAL, J.; DA COSTA, S. S.; DA COSTA, C. M. L.; DA CUNHA, I. W.; CYPRIANO, M.; DE TOLEDO, S. R. C.; DE SOUZA, J. E. S.; et al. Genomic Studies in Hepatoblastoma: Insight into Somatic Mutations Using Array-CGH Analysis and Whole-Exome Sequencing. PEDIATRIC BLOOD & CANCER, v. 64, p. 2-pg., 2017-11-01. (13/08028-1, 16/04785-0)

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; et al. 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. (15/06281-7, 09/00898-1, 16/04785-0, 13/08028-1, 11/24007-9)

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.; et al. Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients. FRONTIERS IN ONCOLOGY, v. 10, MAY 5 2020. (13/08028-1, 18/05961-2, 16/04785-0, 17/11212-0, 16/23462-8, 18/21047-9)

AGUIAR, TALITA; RODRIGUES, TATIANE; LIMA DA COSTA, CECILIA MARIA; WERNECK, ISABELA; CYPRIANO, MONICA; CAMINADA DE TOLEDO, SILVIA REGINA; SANTANA DE SOUZA, JORGE ESTEFANO; TOJAL, ISRAEL; CARRARO, DIRCE M.; ROSENBERG, CARLA; et al. Insights into the somatic mutation burden of hepatoblastomas using whole exome sequencing.. Clinical Cancer Research, v. 24, n. 1, p. 1-pg., 2018-01-01. (13/08028-1, 16/04785-0)