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 highresolution 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 ¼ 0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study

“…Similar results with regard to the prognostic relevance of additional karyotype alterations were published by the German --Austrian MDS Group. 17 Using comparative genome hybridization, Evers et al 18 and Thiel et al 19 were also able to show the prognostic value of additional abnormalities. Moreover, it has been shown recently that the status of p53 expression at baseline is an important driver for disease progression in del(5q).…”

Section E6.1–6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow–acquired chromosomal abnormalities

“…CMA analysis is proving to be very useful in uncovering these genomic aberrations in MDS. 19,20 Examples include cryptic 5q deletions distal to the EGR1 gene (5q31). These can be missed by G-banded chromosome and FISH analyses.…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…Emerging data demonstrate that MDS exhibits abundant CNAs and CNLOH, often in the setting of a normal metaphase karyotype and no previously identified clonal marker [Heinrichs et al, 2009;Thiel et al, 2011;Tiu et al, 2011b]. Tiu et al (2011a) proposed a new prognostic risk score, integrating SNP array results in order to improve risk stratification for patients with MDS.…”