Fanconi anaemia genes and susceptibility to cancer

Abstract

Fanconi anaemia (FA) is a rare recessive disorder associated with chromosomal fragility, aplastic anaemia, congenital abnormalities and a high risk of cancer, including acute myeloid leukaemia and squamous cell carcinomas. The identification of 11 different FA genes has revealed a complex web of interacting proteins that are involved in the recognition or repair of DNA interstrand crosslinks and perhaps other forms of DNA damage. Bi-allelic mutations in BRCA2 are associated with a rare and highly cancer-prone form of FA, and the DNA helicase BRIP1 (formerly BACH1) is mutated in FA group J. There is little convincing evidence that FA heterozygotes are at increased risk of cancer, but larger studies are needed to address the possibility of modest risk effects. Somatic inactivation of the FA pathway by mutation or epigenetic silencing has been observed in several different types of sporadic cancer, and this may have important implications for targeted chemotherapy. Inhibition of this pathway represents a possible route to sensitization of tumours to DNA crosslinking drugs such as cisplatin.

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

“…Focal co-localization with HRassociated Rad51 as well as the BRCA1, BRCA2/ FANCD1 and BACH1/BRIP1/FANCJ breast cancer susceptibility gene products is observed, and FA pathways presumably coordinate DNA replication with HR and translesion synthesis (Niedzwiedz et al, 2004). The loss of such functions is in agreement with the observed chromosomal instability and high cancer incidence in FA patients (Mathew, 2006). In agreement with a requirement for intact FA functions in primary human keratinocytes, lentiviral knockdown of FANCD2 was sufficient for causing a dramatic cellular growth suppression phenotype, perhaps as a result of extensive DNA damage (Figure 1c).…”

“…Even though the incidence of FA is extremely low, scientific interest in FA proteins continues to grow. This is due to the reported physical association of nuclear FA complexes with important known DNA repair proteins, such as BRCA1 and BRCA2, Rad51 and phosphorylated gH2AX, as well as multiple reports on the somatic inactivation of FA pathways in sporadic human cancers (Mathew, 2006). As a consequence of DNA damage or during S phase, a nuclear core complex consisting of FA proteins A, B, C, E, F, G, L, M as well as FAAP24 and FAAP100 are assembled (Wang, 2007).…”

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita

“…10 These are primarily skin, head and neck, and anogenital cancers, 10 resembling what is observed in patients with FA. 40,41 Cancer and pulmonary disease follow BMF as the causes of premature mortality for DC patients. 9,10 It is important to identify these patients early in life in order to screen for BMF, MDS, AML and solid tumors.…”

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

“…The following human transformed fibroblast cell lines were used in this study: PD20 (FANCD2−/−), PD20 retrovirally corrected with pMMp-FANCD2 cDNA, FANCA−/ − (PD220)-transformed fibroblasts and corrected counterparts (FA consortium), 4 FANC-G-and FANC-Gcorrected primary fibroblasts (gift of Dr. D. Schindler, Wurzburg University, Wurzburg, Germany). In addition, we used primary human fibroblasts derived from a healthy individual and lymphoblastoid cells from a non-FA patient [FANCL (EUFA 868), FANCJ (LFA 177), and FANCA (LFA 82)-transformed lymphoblastoid cells].…”

“…Currently, 13 FA complementation groups are known to exist, each of which represents a FA subtype abbreviated as A (FANCA), B (FANCB), C (FANCC), D1 (FANCD1/BRCA2), D2 (FANCD2), E (FANCE), F (FANCF), G (FANCG), I (FANCI/KIAA1794), J (FANCJ/BRIP1), L (FANCL), M (FANCM), and N (FANCN; refs. 3,4). With the exception of FANCD2 and FANCI, the encoded FA proteins have no similarities with each other but cooperate in a common FA/BRCA pathway by the formation of subnuclear and nuclear complexes, where activation by monoubiquitinylation of FANCD2 and FANCI seems to orchestrate a cascade of events in response to DNA damage (5).…”