Prognostic significance of mutation type and chromosome fragility in Fanconi anemia

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.

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Publication Details

Journal
American Journal of Hematology
Published
2024-11-19
DOI
https://doi.org/10.1002/ajh.27520
Citations
12
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
2.81

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article

Prognostic significance of mutation type and chromosome fragility in Fanconi anemia

Fátima Ibáñez, Isabel Cuesta, Jaime Verdú‐Amorós, Juan Pablo Trujillo‐Quintero et al.
12 citations
American Journal of Hematology
DNA Repair Mechanisms
2.81
article

Prognostic significance of mutation type and chromosome fragility in Fanconi anemia

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

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.

American Journal of HematologyVol. 100(2)
Goethe University Frankfurt (DE), Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), Hospital Universitario de Canarias (ES), Instituto de Salud Carlos III (ES), Hospital de Sant Pau (ES), Hospital General Universitario Gregorio Marañón (ES), Hospital Universitari i Politècnic La Fe (ES), BioCruces Health research Institute (ES), Spanish National Cancer Research Centre (ES), Hospital Universitario Virgen Macarena (ES), Hospital General Universitario Morales Meseguer (ES), Hospital de Basurto (ES), Complejo Hospitalario Universitario de Santiago (ES), University Hospital Mútua de Terrassa (ES), Complejo Hospitalario de Salamanca (ES), Vall d'Hebron Institut de Recerca (ES), Hospital La Paz Institute for Health Research (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Institut Català d'Oncologia (ES), Hospital Regional Universitario de Málaga (ES), Hospital Universitario Quirónsalud Madrid (ES), Hospital San Pedro de Alcántara (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Obispo Polanco (ES), Hospital Infantil Universitario Niño Jesús (ES), Instituto de Investigación Marqués de Valdecilla (ES), Hospital Clínic de Barcelona (ES), Corporació Sanitària Parc Taulí (ES), Hospital Universitario de Burgos (ES), Hospital Universitario Virgen de las Nieves (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Hospital Materno-Infantil (ES), Hospital Universitario de La Princesa (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Central de Asturias (ES), Institute of Research and Innovation Parc Tauli (ES), Centro de Implantología Cirugía Oral y Maxilofacial (ES), Hospital Universitario Puerto Real (ES), Duran i Reynals Hospital (ES), Hospital Universitario Puerta del Mar (ES), Hospital General Universitario de Albacete (ES), Hospital Universitario Virgen de la Arrixaca (ES), Complejo Hospitalario Torrecárdenas (ES), Banc de Sang i Teixits (ES), Hospital Universitario Son Espases (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), Hospital Jerez Puerta del Sur (ES), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Instituto de Investigación de Enfermedades Raras (ES), Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES), Institut de Recerca Sant Pau (ES), Universidad de Sevilla (ES)
Fanconi Anemia Research Fund, Ministerio de Ciencia, Innovación y Universidades, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Agencia Estatal de Investigación
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Openalex Percentile: Top 9%
DNA Repair Mechanisms
2.81
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