Frontiers in Genetics (Apr 2022)
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,
- Talita Aguiar,
- Talita Aguiar,
- Anne Teixeira,
- Anne Teixeira,
- Marília O. Scliar,
- Juliana Sobral de Barros,
- Juliana Sobral de Barros,
- Renan B. Lemes,
- Renan B. Lemes,
- Silvia Souza,
- Silvia Souza,
- Giovanna Tolezano,
- 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,
- Estela Novak,
- Lilian Maria Cristofani,
- Sofia M. Miura Sugayama,
- Vicente Odone,
- Isabela Werneck Cunha,
- Cecilia Maria Lima da Costa,
- Carla Rosenberg,
- Carla Rosenberg,
- Ana Krepischi,
- Ana Krepischi
Affiliations
- Talita Aguiar
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Talita Aguiar
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Talita Aguiar
- Columbia University Irving Medical Center, New York, NY, United States
- Anne Teixeira
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Anne Teixeira
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Marília O. Scliar
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Juliana Sobral de Barros
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Juliana Sobral de Barros
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Renan B. Lemes
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Renan B. Lemes
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Silvia Souza
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Silvia Souza
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Giovanna Tolezano
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Giovanna Tolezano
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Fernanda Santos
- Department of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil
- Israel Tojal
- International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil
- Monica Cypriano
- GRAACC—Grupo de Apoio Ao Adolescente e Criança Com Câncer, Federal University of São Paulo, São Paulo, Brazil
- Silvia Regina Caminada de Toledo
- GRAACC—Grupo de Apoio Ao Adolescente e Criança Com Câncer, Federal University of São Paulo, São Paulo, Brazil
- Eugênia Valadares
- Benjamim Guimarães Foundation - Department of Pediatrics Hospital da Baleia, Belo Horizonte, Brazil
- Raquel Borges Pinto
- Department of Genetics, Hospital da Criança Conceição, Hospitalar Conceição Group, Porto Alegre, Brazil
- Osvaldo Afonso Pinto Artigalas
- Department Pediatric Gastroenterology, Hospital da Criança Conceição, Hospitalar Conceição Group, Porto Alegre, Brazil
- Joaquim Caetano de Aguirre Neto
- 0Paediatric Haemato-oncology, Hospital Santa Casa de Belo Horizonte, Belo Horizonte, Brazil
- Estela Novak
- 1Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
- Estela Novak
- 2Molecular Genetics—Foundation Pro Sangue Blood Center of São Paulo, São Paulo, Brazil
- Lilian Maria Cristofani
- 1Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
- Sofia M. Miura Sugayama
- 3Department of Pediatric, Faculty of Medicine of the University of São Paulo, São Paulo, Brazil
- Vicente Odone
- 1Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
- Isabela Werneck Cunha
- 4Department of Pathology, Rede D’OR-São Luiz, São Paulo, Brazil
- Cecilia Maria Lima da Costa
- Department of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil
- Carla Rosenberg
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Carla Rosenberg
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Ana Krepischi
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- Ana Krepischi
- Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
- DOI
- https://doi.org/10.3389/fgene.2022.858396
- Journal volume & issue
-
Vol. 13
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
