Prognostic significance of mutation type and chromosome fragility in Fanconi anemia
Marı́a José Ramı́rez, Roser Pujol, Jordi Minguillón, Massimo Bogliolo, Ilaria Persico, Debora Cavero, Aurora de la Cal, Paula Rı́o, Susana Navas Navarro, José Antonio Casado, Almudena Bailador, Antonio de la Fuente, Miguel López de Heredia, F.M. Almazán-Fernández, María Luisa Antelo, Bienvenida Argilés, Isabel Badell, Marta Bernués, Cristina Beléndez, Mar Bermúdez, Marta Bernués, María Isabel Buedo, Estela Carrasco, Albert Català, Dolors Costa, Isabel Cuesta, Rafael Fernández‐Delgado, Ana Fernández‐Teijeiro, Á Figuera, Marta Rizo García, Ainhoa Gondra, Macarena González, Soledad González Muñíz, Inés Hernández‐Rodríguez, Fátima Ibáñez, Nicholas Kelleher, Francisco Lendínez, Monica López‐Duarte, Ricardo López Almaraz, Inmaculada Marchante, Carmen Mendoza, J. M. Nieto, Emilio Ojeda, Salvador Payán‐Pernía, Irene Peláez, Inmaculada Pérez de Soto, Raquel Portugal, María A. Ramos‐Arroyo, Alexandra Regueiro, Ana Rodríguez, Jordi Rosell, Raquel Saez, José Luis Sánchez Sánchez, Martha Alejandra Morales‐Sánchez, MªLeonor Senent, Maria C. Tapia, Juan Pablo Trujillo‐Quintero, José Manuel Vagace, Jaime Verdú‐Amorós, Victória Verdugo, Isabel Vidales, Jasson Villarreal, Cristina Díaz de Heredia, Julián Sevilla, Juan A. Bueren, Jordi Surrallés
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 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. Clinical Trial Registration number: NCT06490510.