Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants

Adachi, Daiki; Oda, Tsukasa; Yagasaki, Hiroshi; Nakasato, Keiko; Taniguchi, Toshiyasu; D’Andrea, Alan D.; Asano, Shigetaka; Yamashita, Takayuki

doi:10.1093/hmg/11.25.3125

Cited by 72 publications

(101 citation statements)

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“…A comparison of the more common FA groups A, C and G found a higher incidence of acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) in FA-G (Faivre et al, 2000), and FANCD1/BRCA2 mutations produce a particularly cancer-prone phenotype (see below). Variations in clinical severity are consistent with the finding that different patient-derived mutations in the FANCA gene have variable effects on the function of the FA pathway (Adachi et al, 2002). The clinical phenotype may also be modified by somatic mosaicism in which a functional FANC allele is generated by intragenic recombination or gene conversion in compound heterozygotes or, remarkably, in mutation homozygotes by a compensatory secondary mutation in cis which restored the function of the mutant allele (Waisfisz et al, 1999).…”

Section: Genetics Of Fasupporting

confidence: 79%

Fanconi anaemia genes and susceptibility to cancer

2006

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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.

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Section: Genetics Of Fasupporting

confidence: 79%

Fanconi anaemia genes and susceptibility to cancer

2006

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“…7,18 Taking advantage of molecular data from revertant cell lines, we were also able to support the deleterious effect of p.Ala118Pro and p.His913Pro. Moreover, p.Leu684Pro was identified as a de novo mutation in FA48 (Online Supplementary Table S1), strongly suggesting its pathogenetic role.…”

Section: Discussionmentioning

confidence: 84%

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o napproximately 80% of FA patients worldwide, will not be successful in at least 20%. Secondly, there is a wide spectrum of mutations, mainly private, spanning the entire genes, including intragenic deletions, as frequently observed in FANCA (http://www.rockefeller.edu/fanconi/). Since mutational screening would largely benefit from a preliminary knowledge of the candidate gene, complementation by cell fusion or by viral transduction, as well as protein analyses, have been established as screening strategies to identify the putative gene that is defective. 6,7 Thirdly, a false negative or inconclusive chromosomal breakage test might occur in patients who develop hematopoietic mosaicism due to reversion of the cellular FA phenotype. 8,9 This phenomenon arises if a spontaneous genetic event reconstitutes normal protein activity of one allele. Since it is unlikely that the same somatic event will also occur in primary skin fibroblasts, these cells are often used for mutational screening.In this paper, we report the molecular data of 100 FA families enrolled into the National Network of the Marrow Failure Study Group of the Italian Association of Pediatric Hematology and Oncology. This cohort consists of 76 new families, as well as 24 families that have been described in previous reports. 10,11 Methods Patients, cell lines, and DNA samplesPatients with a positive chromosomal breakage test were included in this study for molecular screening of FA genes by the National Network of the Marrow Failure Study Group of the Italian Association of Pediatric Hematology and Oncology. All the subjects or their legal guardians gave written informed consent to the investigation, according to the Declaration of Helsinki. Protocols were approved by the ethics review boards of the institutions that enrolled the patients. DNA was extracted from peripheral blood, lymphoblastoid cell lines and/or primary fibroblasts. Complementation and Western blot analysesLymphoblast cell lines, peripheral blood T lymphocytes or primary fibroblasts were transduced with retroviral expressing the cDNAs for FANCA, FANCC or FANCG as previously reported. 6 Complementation was considered to occur when the viability of the transduced cells increased by more than 20% that of controls at at least three different mitomycin C concentrations. Western blot analysis of FANCD2 using a monoclonal antibody (Santa Cruz, CA, USA; diluted 1:500) was performed as previously described. 10 Sequencing analysis and multiplex ligation-dependent probe amplificationThe coding exons of the FA genes and their flanking regions were sequenced using a set of oligonucleotides (the primer sequences are available upon request) according to standard procedures. 10 Six samples were first analyzed using the Ion PGM TM system for next generation sequencing of the 16 FA genes according to the manufacturer's protocols (Life Technologies). Variants with minor allele frequency less than 1% were then confirmed by Sanger sequencing as above. N...

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“…This is in agreement with previous studies for some particular missense mutations. 43,44 Therefore, DNA damage signaling and other possible nuclear FANCA functions are completely abolished in all FANCA mutants irrespective of the mutation type.…”

Section: Discussionmentioning

confidence: 98%