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

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.

[1]  U. Klein,et al.  Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines. , 2012, Blood.

[2]  N. Pochet,et al.  Germline copy number variation associated with Mendelian inheritance of CLL in two families , 2012, Leukemia.

[3]  David T. W. Jones,et al.  Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations , 2012, Cell.

[4]  L. Pasqualucci,et al.  Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. , 2011, Blood.

[5]  E. Giné,et al.  Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia , 2011, Nature Genetics.

[6]  L. Pasqualucci,et al.  Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. , 2011, Blood.

[7]  A. Sivachenko,et al.  SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. , 2011, The New England journal of medicine.

[8]  M. Kaminski,et al.  Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. , 2011, Blood.

[9]  P. Ouillette,et al.  The Prognostic Significance of Various 13q14 Deletions in Chronic Lymphocytic Leukemia , 2011, Clinical Cancer Research.

[10]  Hanna Göransson,et al.  Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia , 2011, Haematologica.

[11]  Juliane C. Dohm,et al.  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia , 2011, Nature.

[12]  L. Pasqualucci,et al.  Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation , 2011, The Journal of experimental medicine.

[13]  N. Carter,et al.  Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development , 2011, Cell.

[14]  Harvey Herschman,et al.  B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia , 2010, Proceedings of the National Academy of Sciences.

[15]  A. Berrebi,et al.  Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial , 2010, The Lancet.

[16]  Andrea Califano,et al.  The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. , 2010, Cancer cell.

[17]  J. Staaf,et al.  Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients , 2010, Leukemia.

[18]  ONSTANZE,et al.  GENOMIC ABERRATIONS AND SURVIVAL IN CHRONIC LYMPHOCYTIC LEUKEMIA , 2010 .

[19]  H. Döhner,et al.  From pathogenesis to treatment of chronic lymphocytic leukaemia , 2010, Nature Reviews Cancer.

[20]  H. Döhner,et al.  TP53 Mutations and Outcome After Fludarabine and Cyclophosphamide (FC) or FC Plus Rituximab (FCR) in the CLL8 Trial of the GCLLSG. , 2009 .

[21]  J. Downing,et al.  Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia , 2009, Proceedings of the National Academy of Sciences.

[22]  Cheng Cheng,et al.  Reference alignment of SNP microarray signals for copy number analysis of tumors , 2009, Bioinform..

[23]  James R. Downing,et al.  Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia , 2008, Science.

[24]  Axel Benner,et al.  Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. , 2008, Blood.

[25]  G. Mufti,et al.  Whole genome scanning as a cytogenetic tool in hematologic malignancies. , 2008, Blood.

[26]  Francisco Vega,et al.  MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis , 2008, British journal of haematology.

[27]  Christopher B. Miller,et al.  BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros , 2008, Nature.

[28]  Remco Dijkman,et al.  Novel and highly recurrent chromosomal alterations in Sézary syndrome. , 2008, Cancer research.

[29]  S. Ogawa,et al.  Molecular allelokaryotyping of early‐stage, untreated chronic lymphocytic leukemia , 2008, Cancer.

[30]  Terence P. Speed,et al.  Estimation and assessment of raw copy numbers at the single locus level , 2008, Bioinform..

[31]  R. Siebert,et al.  Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  T Hamblin,et al.  Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial , 2007, The Lancet.

[33]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[34]  Jens Timmer,et al.  Using High-density Snp Arrays Genome-wide Analysis of Dna Copy Number Changes and Loh in Cll , 2022 .

[35]  A. Wynshaw-Boris,et al.  Inflammatory Disease and Lymphomagenesis Caused by Deletion of the Myc Antagonist Mnt in T Cells , 2006, Molecular and Cellular Biology.

[36]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[37]  Cheng Li,et al.  dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data , 2004, Bioinform..

[38]  Gunnar Wrobel,et al.  Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Aref,et al.  c-Myc oncogene and Cdc25A cell activating phosphatase expression in non-Hodgkin's lymphoma. , 2003, Hematology.

[40]  A. Ferrer,et al.  Abnormal expression of apoptosis‐related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma , 2003, British journal of haematology.

[41]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A Benner,et al.  Genomic aberrations and survival in chronic lymphocytic leukemia. , 2000, The New England journal of medicine.

[43]  R. Eisenman,et al.  The Myc/Max/Mad network and the transcriptional control of cell behavior. , 2000, Annual review of cell and developmental biology.

[44]  N. Jenkins,et al.  Mga, a dual‐specificity transcription factor that interacts with Max and contains a T‐domain DNA‐binding motif , 1999, The EMBO journal.

[45]  T. Stankovic,et al.  Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia , 1999, The Lancet.

[46]  E. Zabarovsky,et al.  Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia , 1997, Oncogene.

[47]  R. Eisenman,et al.  Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites. , 1997, Genes & development.

[48]  M. James,et al.  Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11q22.3-923.1 in lymphoproliferative disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  A Benner,et al.  p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. , 1995, Blood.

[50]  G. Gaidano,et al.  p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. , 1991, Proceedings of the National Academy of Sciences of the United States of America.