title: Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance.
abstract: About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a high-resolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.
authors.affiliation: Institute of Human Genetics and Anthropology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Thiel
authors.forename: M
authors.initials: M
authors.lastname: Beier
authors.forename: D
authors.initials: D
authors.lastname: Ingenhag
authors.forename: K
authors.initials: K
authors.lastname: Servan
authors.forename: M
authors.initials: M
authors.lastname: Hein
authors.forename: V
authors.initials: V
authors.lastname: Moeller
authors.forename: B
authors.initials: B
authors.lastname: Betz
authors.forename: B
authors.initials: B
authors.lastname: Hildebrandt
authors.forename: C
authors.initials: C
authors.lastname: Evers
authors.forename: U
authors.initials: U
authors.lastname: Germing
authors.forename: B
authors.initials: B
authors.lastname: Royer-Pokora
mesh_terms: D000368:Aged; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012008:Recurrence
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human