title: Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia.
abstract: Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Development Guy's, King's and St Thomas' School of Medicine, King's College London, Guy's Hospital, London, UK. mtischkowitz@doctors.org.uk
authors.forename: M D
authors.initials: MD
authors.lastname: Tischkowitz
authors.forename: N V
authors.initials: NV
authors.lastname: Morgan
authors.forename: D
authors.initials: D
authors.lastname: Grimwade
authors.forename: C
authors.initials: C
authors.lastname: Eddy
authors.forename: S
authors.initials: S
authors.lastname: Ball
authors.forename: I
authors.initials: I
authors.lastname: Vorechovsky
authors.forename: S
authors.initials: S
authors.lastname: Langabeer
authors.forename: R
authors.initials: R
authors.lastname: Stöger
authors.forename: S V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: C G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005091:Exons; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D011506:Proteins