Abstract
Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.
Highlights
Fanconi anaemia (FA) is a complex inherited chromosomal instability disorder with congenital and developmental abnormalities, and cancer predisposition [1,2]
FA-associated bone marrow failure can transform to acute myeloid leukaemia (AML), which is often encountered in later childhood, the second or even third decade
The discovery of BRCA1/2 pathogenic variants underlying FA-like disorders puts the efforts of understanding FA on a cellular level in the context of the DNA damage response, and clinically in the context of inherited cancer predisposition
Summary
Fanconi anaemia (FA) is a complex inherited chromosomal instability disorder with congenital and developmental abnormalities, and cancer predisposition [1,2]. FA caused by bi-allelic BRCA2 PGVs does not have an obvious sex preference and is in most cases associated with a severe phenotype, often with clinical features in the combination of the VACTER-L (vertebral, anal, oesophageal, cardiac renal, and radial dysplasia) complex [5,29] Most of these patients develop aggressive malignancies and sometimes multiple cancers very early in life, with a cancer incidence over 90% at the age of 5 years [30]. After the identification of BRCA2 as the gene for which bi-allelic pathogenic variants underlie the mostly severe FA-phenotype in the complementation group FA-D1, in 2015 pathogenic variants in the other main HBOC gene, BRCA1, were identified to cause an FA-like syndrome [15] Individuals of this small but important subgroup of only 10 reported patients display in most cases cellular cross linker hypersensitivity and have clinical features of developmental abnormalities, and severe cancer predisposition [15,41].
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