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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220496
Prognostic significance of mutation type and chromosome fragility in Fanconi anemia
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Fanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA.
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RAMÍREZ DE HARO, María josé, PUJOL, Roser, MINGUILLÓN, Jordi, BOGLIOLO, Massimo, PERSICO, Ilaria, CAVERO, Debora, CAL, Aurora de la, RÍO, Paula, NAVARRO, Susana, CASADO, José antonio, BAILADOR, Almudena, SANCHEZ DE LA FUENTE, Antonio, LÓPEZ DE HEREDIA, Miguel, ALMAZÁN, Francisco, ANTELO, M. luisa, ARGILÉS, Bienvenida, BADELL, Isabel, BARAGAÑO, Marta, BELÉNDEZ, Cristina, BERMÚDEZ, Mar, BERNUÉS, Marta, BUEDO, María isabel, CARRASCO, Estela, CATALÀ, Albert, COSTA, Dolors, CUESTA, Isabel, FERNANDEZ DELGADO, Rafael, FERNÁNDEZ TEIJEIRO, Ana, FIGUERA, Ángela, GARCÍA, Marta, GONDRA, Ainhoa, GONZÁLEZ, Macarena, GONZÁLEZ MUÑIZ, Soledad, HERNÁNDEZ RODRÍGUEZ, Ines, IBAÑEZ, Fátima, KELLEHER, Nicholas john, LENDÍNEZ, Francisco, LÓPEZ DUARTE, Mónica, LÓPEZ ALMARAZ, Ricardo, MARCHANTE, Inmaculada, MENDOZA, Carmen, NIETO, José, OJEDA, Emilio, PAYÁN PERNÍA, Salvador, PELÁEZ, Irene, PÉREZ DE SOTO, Inmaculada, PORTUGAL, Raquel, RAMOS ARROYO, María a., REGUEIRO, Alexandra, RODRÍGUEZ, Ana, ROSELL, Jordi, SAEZ, Raquel, SÁNCHEZ, José, SÁNCHEZ, Martha, SENENT, M. leonor, TAPIA, María, TRUJILLO QUINTERO, Juan pablo, VAGACE, José manuel, VERDÚ AMORÓS, Jaime, VERDUGO, Victória, VIDALES, Isabel, VILLARREAL, Jasson, DÍAZ DE HEREDIA, Cristina, SEVILLA, Julián, BUEREN, Juan antonio, SURRALLÉS I CALONGE, Jordi. Prognostic significance of mutation type and chromosome fragility in Fanconi anemia. _American Journal of Hematology_. 2024. Vol. 100, núm. 2, pàgs. 272-284. [consulta: 25 de gener de 2026]. ISSN: 1096-8652. [Disponible a: https://hdl.handle.net/2445/220496]