High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations

• Published in: Blood 2012-12, Vol.120 (24), p.4783-4794
• Main Authors: Edelmann, Jennifer, Holzmann, Karlheinz, Miller, Florian, Winkler, Dirk, Bühler, Andreas, Zenz, Thorsten, Bullinger, Lars, Kühn, Michael W.M., Gerhardinger, Andreas, Bloehdorn, Johannes, Radtke, Ina, Su, Xiaoping, Ma, Jing, Pounds, Stanley, Hallek, Michael, Lichter, Peter, Korbel, Jan, Busch, Raymonde, Mertens, Daniel, Downing, James R., Stilgenbauer, Stephan, Döhner, Hartmut
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chromosome Aberrations; DNA Copy Number Variations; Female; Gene Expression Profiling - methods; Genomics - methods; Hematologic and hematopoietic diseases; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Male; Medical sciences; Mutation; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Tumor Suppressor Protein p53 - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-04-423517

To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism–array analysis using Affymetrix Version 6.0 on 353 samples from untreated patients entered in the CLL8 treatment trial. Based on paired-sample analysis (n = 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.21 (5% of patients) to a segment 486 kb proximal to the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4% of patients), with the smallest deletion (70.48 kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one CLL patient lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also deleted recurrently.