title: Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions.
abstract: 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 CEBPα 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.
authors.affiliation: Team Genome and Cancer, Hematology Laboratory Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Quentin
authors.forename: Wendy
authors.initials: W
authors.lastname: Cuccuini
authors.forename: Raphael
authors.initials: R
authors.lastname: Ceccaldi
authors.forename: Olivier
authors.initials: O
authors.lastname: Nibourel
authors.forename: Corinne
authors.initials: C
authors.lastname: Pondarre
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pagès
authors.forename: Nadia
authors.initials: N
authors.lastname: Vasquez
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubois d'Enghien
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Régis
authors.initials: R
authors.lastname: Peffault de Latour
authors.forename: Vanderson
authors.initials: V
authors.lastname: Rocha
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Dalle
authors.forename: Pascale
authors.initials: P
authors.lastname: Schneider
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
authors.forename: Gérard
authors.initials: G
authors.lastname: Michel
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
mesh_terms: D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C000716967:NPM1 protein, human; C493728:RUNX1 protein, human; D000090243:Nucleophosmin