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Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort

Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure and an increased risk of cancer. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared...

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Detalles Bibliográficos
Autores principales: Altintas, Burak, Giri, Neelam, McReynolds, Lisa J., Best, Ana, Alter, Blanche P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827153/
https://www.ncbi.nlm.nih.gov/pubmed/35417938
http://dx.doi.org/10.3324/haematol.2021.279981
Descripción
Sumario:Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure and an increased risk of cancer. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared across the genes, FA/BRCA DNA repair pathways (upstream, ID complex and downstream), and type of pathogenic variants (hypomorphic or null). We explored differences between the patients evaluated in our clinic (clinic cohort) and those who provided data remotely (field cohort). Patients with variants in the upstream complex pathway had less severe phenotype, lacking VACTERL-H (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal/duodenal atresia, Renal, Limb, Hydrocephalus) association and/or PHENOS (Pigmentation, small Head, small Eyes, Neurologic, Otologic, Short stature) features. ID complex was associated with VACTERL-H. The clinic cohort had more PHENOS features than the field cohort. PHENOS was associated with increased risk of bone marrow failure, and VACTERL-H with hypothyroidism. The cumulative incidences of severe bone marrow failure, solid tumors and leukemia as the first event were 70%, 20% and 6.5%, respectively. Head and neck and gynecological cancers were the most common solid tumors, with a further increased risk after hematopoietic cell transplantation. Among patients with FANCA, variants in exons 27-30 were associated with a higher frequency of solid tumors. Overall the median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had the poorest survival. Patients with variants in the upstream complex had better survival than those with variants in ID or the downstream complex (P=0.001 and P=0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding its clinical management.