Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes

Talita Aguiar; Anne Teixeira; Marília O Scliar; Juliana Sobral de Barros; Renan B Lemes; Silvia Souza; Giovanna Tolezano; Fernanda Santos; Israel Tojal; Monica Cypriano; Silvia Regina Caminada de Toledo; Eugênia Valadares; Raquel Borges Pinto; Osvaldo Afonso Pinto Artigalas; Joaquim Caetano de Aguirre Neto; Estela Novak; Lilian Maria Cristofani; Sofia M Miura Sugayama; Vicente Odone; Isabela Werneck Cunha; Cecilia Maria Lima da Costa; Carla Rosenberg; Ana Krepischi

doi:10.3389/fgene.2022.858396

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes

Front Genet. 2022 Apr 12:13:858396. doi: 10.3389/fgene.2022.858396. eCollection 2022.

Authors

Talita Aguiar^{1

2

3}, Anne Teixeira^{1

2}, Marília O Scliar², Juliana Sobral de Barros^{1

2}, Renan B Lemes^{1

2}, Silvia Souza^{1

2}, Giovanna Tolezano^{1

2}, Fernanda Santos⁴, Israel Tojal⁵, Monica Cypriano⁶, Silvia Regina Caminada de Toledo⁶, Eugênia Valadares⁷, Raquel Borges Pinto⁸, Osvaldo Afonso Pinto Artigalas⁹, Joaquim Caetano de Aguirre Neto¹⁰, Estela Novak^{11

12}, Lilian Maria Cristofani¹¹, Sofia M Miura Sugayama¹³, Vicente Odone¹¹, Isabela Werneck Cunha¹⁴, Cecilia Maria Lima da Costa⁴, Carla Rosenberg^{1

2}, Ana Krepischi^{1

2}

Affiliations

¹ Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
² Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
³ Columbia University Irving Medical Center, New York, NY, United States.
⁴ Department of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil.
⁵ International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil.
⁶ GRAACC-Grupo de Apoio Ao Adolescente e Criança Com Câncer, Federal University of São Paulo, São Paulo, Brazil.
⁷ Benjamim Guimarães Foundation - Department of Pediatrics Hospital da Baleia, Belo Horizonte, Brazil.
⁸ Department of Genetics, Hospital da Criança Conceição, Hospitalar Conceição Group, Porto Alegre, Brazil.
⁹ Department Pediatric Gastroenterology, Hospital da Criança Conceição, Hospitalar Conceição Group, Porto Alegre, Brazil.
¹⁰ Paediatric Haemato-oncology, Hospital Santa Casa de Belo Horizonte, Belo Horizonte, Brazil.
¹¹ Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil.
¹² Molecular Genetics-Foundation Pro Sangue Blood Center of São Paulo, São Paulo, Brazil.
¹³ Department of Pediatric, Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.
¹⁴ Department of Pathology, Rede D'OR-São Luiz, São Paulo, Brazil.

Abstract

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Keywords: CYP1A1; DNA repair; ERCC5; MSH2; MUTYH; VHL; cancer predisposition; hepatoblastoma.

Copyright © 2022 Aguiar, Teixeira, Scliar, Sobral de Barros, Lemes, Souza, Tolezano, Santos, Tojal, Cypriano, Caminada de Toledo, Valadares, Borges Pinto, Pinto Artigalas, Caetano de Aguirre Neto, Novak, Cristofani, Miura Sugayama, Odone, Cunha, Lima da Costa, Rosenberg and Krepischi.