Fanconi anemia

Abstract

What is it? Fanconi anemia (FA) is an autosomal recessive human disease characterized by congenital malformations, bone marrow failure and cancer. FA patients often develop leukemia and/or squamous cell carcinomas of the head and neck or gynecologic system. FA cells are hypersensitive to DNA crosslinking agents, such as mitomycin C (MMC) or diepoxybutane (DEB), and the syndrome is believed to result from a defect in DNA repair. The genetics of FA? From somatic cell fusion studies, FA has at least eight complementation groups. Seven FA genes have been cloned, corresponding to subtypes A, C, D1, D2, E, F and G. Interestingly, the FANCD1 gene is identical to the breast cancer susceptibility gene BRCA2. Biallelic disruption of any of these seven FA genes results in the common clinical and cellular phenotype of FA patients. FANCD2 is the only FA gene with known homologues in invertebrates (Drosophila and CaenorhabditisÊelegans). What is the function of the FA genes? Perhaps not surprisingly, the seven cloned FA proteins interact in a common signaling pathway (Figure 1). In a normal human cell, five of the FA proteins – A, C, E, F and G – form a nuclear complex, required for the monoubiquitination of the downstream FANCD2 protein. After cellular exposure to genotoxic agents, monoubiquitinated (activated) FANCD2 is targeted to nuclear foci which also contain BRCA1 and FANCD1/BRCA2. Any related human syndromes? Other human genetic diseases, such as ataxia telangiectasia (AT) and Nijmegen's breakage syndrome (NBS), also display spontaneous chromosome breakage and cancer predisposition. Interestingly, the ATM and NBS1 proteins interact with elements of the FA/BRCA pathway, perhaps accounting for the partial overlap in these clinical syndromes. What does the FA/BRCA pathway do? Recent evidence indicates that biallelic mutations of BRCA1 or BRCA2 in tumor cells results in a defect in DNA repair by homologous recombination. The FA/BRCA pathway appears to regulate homologous recombination repair during S phase or following DNA damage by crosslinking agents, although the precise function of the downstream monoubiquitinated FANCD2 protein in this process remains unknown. Relevance to cancer in the general population? Like many human cancers, FA cells display chromosome instability and cis-platinum sensitivity. Recent studies indicate that acquired (somatic) disruption of the FA/BRCA pathway can account for these features in some sporadic tumors in the general population, such as ovarian and breast cancer. The FANCF gene, for example, is methylated and inactivated in approximately 20% of epithelial ovarian cancers, perhaps accounting for the cis-platinum sensitivity of at least a subset of these tumors. Demethylation of FANCF and reactivation of the FA/BRCA pathway may result in the emergence of drug-resistant tumor cells. Are FA genes also BRCA genes?BRCA2+/− heterozygotes have an increased risk of developing breast, ovarian and other cancers. As BRCA2 is an FA gene, we speculate that heterozygote carriers of mutations in other FA genes – A, C, D2, E, F and G – may also have an increased cancer risk. The cancer risk may depend on the FA subtype or the presence of specific mutant FA alleles.