Abstract A18: Insights into the somatic mutation burden of hepatoblastomas using whole exome sequencing
Authors: Aguiar Talita , Rodrigues Tatiane , Costa Cecília Maria Lima da , Werneck Isabela , Cypriano Monica , Toledo Silvia Regina Caminada de , Souza Jorge Estefano Santana de , Tojal Israel , Carraro Dirce M , Rosenberg Carla , Krepischi Ana 
Published: May 2019

Hepatoblastomas (HB) are embryonal tumors of the liver with histologic features that resemble different stages of liver differentiation. Molecular data on HB tumorigenesis are still scarce because of its rarity. The identification of molecular pathways involved in HB development can expand the understanding of the connections between disruption of normal differentiation and cancer. Exome sequencing is a powerful tool to identify somatic mutations in tumors, possibly related to cancer development.

We performed a whole-exome sequencing in a discovery cohort of 6 HBs and their paired non-tumoral adjacent liver tissues (capture method 244K Agilent SureSelect Target Enrichment). Bioinformatic analysis of the exome data identified 76 rare somatic variants in coding sequences of 69 genes, which were validated using a target sequencing panel covering the affected genes (SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing Library). These 69 genes and other 48 genes related with HB or cancer were also investigated, in addition to 13 HBs as a validation group. A total of 64 rare somatic mutations in 53 genes were validated in all hepatoblastomas.

Four different pathogenic mutations in the CTNNB1 gene were disclosed in five tumors.

Immunohistochemistry analysis of β-catenin was carried out in eight of the sequenced tumors as well as in a tissue microarray consisting of 19 novel hepatoblastomas cases. The constitutive activity of Wnt-β-catenin pathway, which is caused by the gain-of-function mutations of CTNNB1, was confirmed by the study of protein expression, which shows the accumulation of β-catenin in the nucleus. In addition, CX3CL1 gene was found to be somatically mutated in two different tumors; however, CX3CL1 gene expression was not altered in mutated tumors. We are currently investigating the possible role of CX3CL1 and its receptor (CX3CR1) in hepatoblastomas. Our data highlighted a relatively stable tumoral genome in this type of pediatric liver tumors, which present a small number of potentially pathogenic mutations, a feature that is also a hallmark of adult liver cancer.

Grants: FAPESP (2016/04785-0), FAPESP (2013/08028-1), CNPq (141625/2016-3).

Citation Format: Talita Aguiar, Tatiane Rodrigues, Cecília Maria Lima da Costa, Isabela Werneck, Monica Cypriano, Silvia Regina Caminada de Toledo, Jorge Estefano Santana de Souza, Israel Tojal, Dirce M Carraro, Carla Rosenberg, Ana Krepischi. Insights into the somatic mutation burden of hepatoblastomas using whole exome sequencing [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A18.