title: Chromosomal minimal critical regions in therapy-related leukemia appear different from those of de novo leukemia by high-resolution aCGH.
abstract: Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously "normal" karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML a 40 kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia. In de novo AML, a 1 Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML.
authors.affiliation: Institut de la Santé et de la Reherche Médicale U985, Génétique des tumeurs, Institut Gustave Roussy, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Itzhar
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Saloua
authors.initials: S
authors.lastname: Toujani
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Catherine
authors.initials: C
authors.lastname: Richon
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Véronique
authors.initials: V
authors.lastname: Saada
authors.forename: Anelyse
authors.initials: A
authors.lastname: Bennaceur
authors.forename: Jean Henri
authors.initials: JH
authors.lastname: Bourhis
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: Alain
authors.initials: A
authors.lastname: Bernheim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000139:chemically induced; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations / Q000502:physiology; D005260:Female; D018628:Gene Dosage / Q000502:physiology; D006801:Humans; D007621:Karyotyping / Q000379:methods; D007938:Leukemia / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D007953:Leukemia, Radiation-Induced / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents