Fanconi anaemia (FA) is a complex genetic syndrome associated with risk of congenital malformations, bone marrow failure and cancer. Diagnosis of FA is challenging, as the clinical presentation differs between patients and as other genetic syndromes resemble FA, but a correct diagnosis is needed to optimize clinical care.
All patients with FA have a high risk of cancer, particularly acute myeloid leukaemia (AML) and squamous cell carcinoma. Close expert surveillance is needed from early childhood to detect malignancies early, should they occur.
FA is caused by inherited mutations in any one of at least 21 genes. Genotype–phenotype correlations in FA are beginning to emerge: patients with FA due to biallelic mutations within BRCA1 or BRCA2 have an increased risk of brain tumours in addition to AML.
The FA pathway maximizes efficient DNA damage repair through homologous recombination, coordinates DNA replication and fine-tunes mitotic checkpoints to ensure error-free chromosome segregation during cell division. Therefore, FA proteins guard the genome stability throughout the cell cycle.
Impaired DNA damage repair, faulty DNA replication and chromosome mis-segregation together cause genomic instability in cells deficient in the FA pathway, which may lead to p53-dependent cell cycle arrest and bone marrow failure, or if cell cycle checkpoints fail, this instability may lead to propagation of mutations and cancer.
Acquired mutations in FA genes occur in malignancies in children and adults who do not have FA. As loss of FA pathway activity renders cancer cells sensitive to inhibition of poly(ADP-ribose) polymerase (PARP) and other signalling pathways, knowledge of the FA pathway status in tumours can be utilized for the rational development of personalized precision medicine cancer therapies.
Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2–FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.
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The authors apologize to the colleagues whose work was not cited owing to space limitations. The authors thank the patients with Fanconi anaemia and their families for generously providing cells used for research in the laboratory of G.N. The authors thank G. H. Vance (Indiana University (IU) School of Medicine) for sharing unpublished images of the chromosome breakage test and D. Carlton (IU School of Medicine) for preparing bone marrow aspirate slides. G.N. is a St. Baldrick's scholar and is supported by the US National Institutes of Health (NIH) and Bone Marrow Failure/Barth Syndrome Fund at Riley Children's Foundation.
The authors declare no competing financial interests.
Decreased counts of at least two out of three major blood cell types (white blood cells, red blood cells and platelets).
- Founder effects
A phenomenon whereby a mutation is present in ancestors of a new population through migration to a geographically distant site or cultural isolation. Upon transmission to the future generations, this mutation might contribute to the newly increased frequency of a genetic disease in the population, particularly if this population remains isolated or if inbreeding limits the influx of normal copies of the gene.
- DNA interstrand crosslinking agents
Molecules promoting the formation of covalent bonds between strands of DNA. DNA crosslinks damage the DNA through distortion of the double-helix structure and promote DNA breaks.
- Holliday junctions
Intermediate crossed-strand structures between four strands of DNA that arise during homologous recombination through pairing of homologous DNA strands.
- Synthetic lethal
A situation where simultaneous mutation of two genes leads to cell death, while mutations in either of these genes alone do not kill the cell.
- Standardized incidence ratio
(SIR). The ratio of the observed number of patients to the expected number of cases in a studied population.
- Ataxia-telangiectasia mutated
(ATM). A DNA damage sensor kinase activated upon detection of double-stranded DNA breaks. Inherited ATM mutations cause ataxia telangiectasia, an autosomal recessive syndrome of progressive neurological dysfunction, radiation hypersensitivity, telangiectasia (dilated blood vessels) and high risk of cancer.
- Ataxia telangiectasia and RAD3-related
(ATR). A DNA damage kinase essential for the DNA damage response (DDR) and error-free replication. Loss of ATR causes Seckel syndrome, a rare autosomal recessive disorder associated with short stature, microcephaly and facial dysmorphism.
- Homologous recombination
(HR). A DNA repair mechanism that replaces the lesion with a correct copy created on the template of the undamaged copy of the homologous DNA sequence.
- Non-homologous end-joining
(NHEJ). A DNA repair mechanism that corrects double-stranded DNA breaks without using the homologous DNA template to reconstruct the damaged molecule. It is more prone to errors than repair by homologous recombination.
A protein that recognizes and binds double-stranded DNA breaks to activate their repair via the non-homologous end-joining (NHEJ) pathway.
- TP53-binding protein 1
(TP53BP1). A protein that positively regulates the DNA damage response (DDR) by activating p53 and interacting with other components of the DDR machinery.
A multiprotein structure that forms on centromeres during cell division to capture spindle microtubules and facilitate segregation of chromosomes.
- Mitotic spindle
A highly organized, dynamic cytoskeletal structure that forms from reorganized microtubules, centrosomes and multiple accessory proteins during cell division to segregate chromosomes into the nascent cells.
- Spindle assembly checkpoint
(SAC). A signalling pathway that does not allow chromosome segregation to begin until all chromosomes are correctly attached to the mitotic spindle.
A dynamic structure that governs the separation of the cytoplasmic bridge connecting two cells at the end of cell division. Contraction and separation of the midbody complete the separation of daughter cells.
A complex structure within the chromosome that joins chromatids after replication and provides a platform to establish the kinetochore during cell division.
The generation of additional small nuclei, which may occur upon faulty DNA segregation during cell division.
- Chromosome pulverization
Extensive shattering of chromosomes into very small fragments owing to abnormal replication and cell division.
The final stage of cell division, during which the cytoplasm of the parental cell is divided between two daughter cells as they separate.
Mitosis not followed by cytokinesis, creating cells with double the amount of DNA.
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