A 20-year perspective on the International Fanconi Anemia Registry (IFAR)

TLDR

Fanconi anemia is an autosomal recessive disorder marked by cellular hypersensitivity to DNA cross‑linking agents, cancer predisposition, and a key role for FA proteins in DNA repair, recombination, and cell‑cycle control. The International Fanconi Anemia Registry prospectively collects data on FA patients, providing a large cohort to analyze the natural history of this rare, clinically heterogeneous disorder. Among 754 FA patients, 80 % developed bone marrow failure and 23 % had neoplasms (60 % hematologic, 40 % nonhematologic), with cumulative incidences of 90 %, 33 %, and 28 % by age 40, and multivariate analysis identified FANCC mutations and hematopoietic stem cell transplantation as poor‑risk factors, while complementation group C showed earlier BMF onset and worse survival.

Abstract

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCC mutations (P =.007) and hematopoietic stem cell transplantation (P = <.0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.