期刊
BLOOD
卷 117, 期 15, 页码 E161-E170出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-09-308726
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类别
资金
- Diagnostic de la maladie de Fanconi [AOM05066]
- Agence Nationale de le Recherche
- des maladies rares ausc maladies communes (GENOPAT) [ANR-08-GENO-013-03]
- Institut National du Cancer
- Direction de l'Hospitalisation et de l'Organisation des Soins
- DREAM [09-76-13]
- Association pour la Recherche sur le Cancer
Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBP alpha mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure. (Blood. 2011; 117(15):e161-e170)
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