Center for Clinical and Translational Science

International Fanconi Anemia Registry has entered its thirty sixth year at the Rockefeller University. Started by Dr. Arleen Auerbach, it is now being continued by Dr. Agata Smogorzewska, an Associate Professor and Head of the Laboratory of Genome Maintenance. The lab is studying how DNA is repaired during replication and has spent the last eight years on identifying new Fanconi anemia genes, studying their mechanism of function, and understanding the underlying pathogenesis of the disease. Major effort has been in genotyping all of the participants in the Fanconi anemia registry to permit the genotype-phenotype correlation analysis.

Two recent papers, which concentrate on the mutational spectra of the genes FANCA (Kimble DC et al. Human Mutation 2018) and FANCB (Asur RS et al, Molecular Genetic and Genomic Medicine, 2017), investigate the great diversity of mostly private mutations in FANCA and start to explore the effects of the genotype and somatic mosaicism in patients with FANCB mutations. Access to cell lines that are part of the registry allows the investigators to bridge the knowledge gap between the patient and cellular phenotypes and facilitates insights into the pathology of the disease and the basic biology of DNA repair.

The majority of Fanconi anemia patients require hematopoietic stem cell transplantation in the first decade of life to treat their bone marrow failure. Thereafter, they face the further challenge of developing very early onset, aggressive squamous cell carcinoma (SCC) of the head, neck, and anogenital region. As a result, the Smogorzewska laboratory is now focusing on defining mutational signatures of these tumors from the Fanconi anemia patients. The registry has collected many tumor samples that are being analyzed using next generation sequencing platforms. Preliminary results suggest very heterogeneous and highly unstable genomic landscapes for these tumors. Future studies will concentrate on identifying pathways that are affected in the tumors and possible synthetic lethal interactions that may lead to the development of better therapies of the Fanconi anemia patients. The effort to identify preventive, diagnostic, and treatment modalities for Fanconi anemia tumors has also been a major focus the Fanconi Anemia Research Fund (http://fanconi.org/). Dr. Smogorzewska joined the Fanconi Anemia Research Fund Scientific Advisory Board this year and has set the understanding of tumorigenesis in Fanconi anemia patients as a high priority.