Prognostic significance of mutation type and chromosome fragility in Fanconi anemia.

Fecha de publicación: 19/11/2024

Autores de IIS La Fe

Bienvenida Argiles Aparicio

Autor

Participantes ajenos a IIS La Fe

Ramirez, Maria Jose
Pujol, Roser
Minguillon, Jordi
Bogliolo, Massimo
Persico, Ilaria
Cavero, Debora
de la Cal, Aurora
Rio, Paula
Navarro, Susana
Casado, Jose Antonio
Bailador, Almudena
de la Fuente, Antonio Sanchez
de Heredia, Miguel Lopez
Almazan, Francisco
Antelo, M Luisa
Badell, Isabel
Baragano, Marta
Belendez, Cristina
Bermudez, Mar
Bernues, Marta
Buedo, Maria Isabel
Carrasco, Estela
Catala, Albert
Costa, Dolors
Cuesta, Isabel
Fernandez-Delgado, Rafael
Fernandez-Teijeiro, Ana
Figuera, Angela
Garcia, Marta
Gondra, Ainhoa
Gonzalez, Macarena
Muniz, Soledad Gonzalez
Hernandez-Rodriguez, Ines
Ibanez, Fatima
Kelleher, Nicholas John
Lendinez, Francisco
Lopez, Monica
Lopez-Almaraz, Ricardo
Marchante, Inmaculada
Mendoza, Carmen
Nieto, Jose
Ojeda, Emilio
Payan-Pernia, Salvador
Pelaez, Irene
de Soto, Inmaculada Perez
Portugal, Raquel
Ramos-Arroyo, Maria A
Regueiro, Alexandra
Rodriguez, Ana
Rosell, Jordi
Saez, Raquel
Sanchez, Jose
Sanchez, Martha
Senent, MLeonor
Tapia, Maria
Trujillo-Quintero, Juan Pablo
Vagace, Jose Manuel
Verdu-Amoros, Jaime
Verdugo, Victoria
Vidales, Isabel
Villarreal, Jasson
Diaz-de-Heredia, Cristina
Sevilla, Julian
Bueren, Juan Antonio
Surralles, Jordi

Abstract

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 30years, 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. Clinical Trial Registration number: NCT06490510.