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Fanconi anaemia (FA) is a genetic, life-threatening disorder1,2 featuring progressive bone marrow failure, birth defects, leukaemia, increased incidence of solid tumours, spontaneous chromosomal instability and hypersensitivity to cross-linking reagents.1,2 Because of FA’s relationship to DNA damage hypersensitivity and its association with susceptibility to neoplastic transformation, the FA research field has gained much attention in recent decades, especially after the discovery of the connection between FA and the well-known breast cancer (BRCA) genes.
FA is a very heterogeneous condition clinically, and about 70% of patients display a wide variety of abnormalities, classic among which are missing or misshapen thumbs and radii, kidney, gastrointestine and neurocognitive and developmental delay.3–10 The most important clinical feature of FA is marrow failure in the form of aplastic anaemia, myelodysplastic syndrome or acute myeloid leukaemia (AML).3,4 The number of FA children surviving childhood has greatly increased with the advent of improved outcomes after bone marrow transplantation for bone marrow failure and AML, but those patients surviving until adulthood have to face a greatly increased risk of solid tumours, typically squamous cell carcinomas such as head and neck and gynaecological tumours.11,12
Because FANCD1/BRCA2 conveys an inherited risk of breast, ovarian and pancreatic cancer for individuals carrying a single mutated allele, the FA pathway is thought to be involved in cancer development. Many studies support the notion that somatic inactivation of the FA pathway may contribute to the pathogenesis of sporadic cancers, including AML.13 For pancreatic cancer, although screens for germline mutations in FANCC, FANCA and FANCG failed to detect any pathogenic alleles in familial tumours,14 truncations of FANCC were found in sporadic pancreatic cancers of early-onset cases.15 Expression of FANCF is decreased in most ovarian cancers compared with those in normal ovarian tissue,16 in part because of methylation of the FANCF promoter, suggesting a role for epigenetic modifications in FA tumorigenesis.16 Restoration of this pathway is associated with demethylation of FANCF, leading to acquired cisplatin resistance.6–8