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Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.
Pires, Carolina; Marques, Inês J; Saramago, Ana; Moura, Margarida M; Pojo, Marta; Cabrera, Rafael; Santos, Catarina; Rosário, Francisco; Lousa, Diana; Vicente, João B; Bandeiras, Tiago M; Teixeira, Manuel R; Leite, Valeriano; Cavaco, Branca M.
Afiliación
  • Pires C; Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Marques IJ; NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
  • Saramago A; Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Moura MM; NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
  • Pojo M; Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Cabrera R; Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Santos C; Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Rosário F; Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • Lousa D; Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.
  • Vicente JB; Serviço de Endocrinologia, Hospital da Luz Lisboa, Lisbon, Portugal.
  • Bandeiras TM; Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa, Oeiras, Portugal.
  • Teixeira MR; Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa, Oeiras, Portugal.
  • Leite V; Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal.
  • Cavaco BM; Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.
Int J Cancer ; 2024 Sep 09.
Article en En | MEDLINE | ID: mdl-39251783
ABSTRACT
The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Int J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Int J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos