Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) has a variable clinical course. Presence of specific genomic aberrations has been shown to impact survival outcomes and can help categorize CLL into clinically distinct subtypes. We studied 178 CLL patients enrolled in a prospective study at the University of Michigan, of whom 139 and 39 were previously untreated and previously treated, respectively. We obtained unbiased, high-density, genome-wide measurements of subchromosomal copy number changes in highly purified DNA from sorted CD19(+) cells and buccal cells using the Affymetrix 50kXbaI SNP array platform (Santa Clara, CA). Genomic complexity scores were derived and correlated with the surrogate clinical end points time to first therapy (TTFT) and time to subsequent therapy (TTST): measures of disease aggressiveness and/or therapy efficaciousness. In univariate analysis, progressively increasing complexity scores in previously untreated CLL patients identified patients with short TTFT at high significance levels. Similarly, TTST was significantly shorter in pretreated patients with high as opposed to low genomic complexity. In multivariate analysis, genomic complexity emerged as an independent risk factor for short TTFT and TTST. Finally, algorithmic subchromosomal complexity determination was developed, facilitating automation and future routine clinical application of CLL whole-genome analysis.

[1]  M. Kaminski,et al.  Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia. , 2007, Blood.

[2]  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.

[3]  T. Haferlach,et al.  Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and immunophenotyping , 2007, Leukemia.

[4]  P. Ouillette,et al.  Comprehensive Analysis of Copy Number and Allele Status Identifies Multiple Chromosome Defects Underlying Follicular Lymphoma Pathogenesis , 2007, Clinical Cancer Research.

[5]  A. Hagemeijer,et al.  Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine , 2007, Leukemia.

[6]  John C Reed,et al.  Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[8]  Thomas S. Lin,et al.  Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. , 2007, Blood.

[9]  R. Kanaar,et al.  DNA double-strand break repair: all's well that ends well. , 2006, Annual review of genetics.

[10]  T. Haferlach,et al.  Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: A study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression. , 2006, Blood.

[11]  T. Shanafelt,et al.  Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[13]  F. Lo Coco,et al.  Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. , 2006, Blood.

[14]  R. Houlston,et al.  Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. , 2006, Blood.

[15]  C. Mayr,et al.  Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. , 2006, Blood.

[16]  J. Gribben,et al.  Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. , 2005, Blood.

[17]  T. Stankovic,et al.  Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. , 2005, Blood.

[18]  Shigeru Chiba,et al.  A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. , 2005, Cancer research.

[19]  A. López-Guillermo,et al.  Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Jing Huang,et al.  Dynamic model based algorithms for screening and genotyping over 100K SNPs on oligonucleotide microarrays , 2005, Bioinform..

[21]  Ash A. Alizadeh,et al.  Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. , 2004, Blood.

[22]  Arthur Weiss,et al.  ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. , 2004, The New England journal of medicine.

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

[24]  Luc Girard,et al.  An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. , 2004, Cancer research.

[25]  K. Naka,et al.  DNA damage tumor suppressor genes and genomic instability. , 2004, Current opinion in genetics & development.

[26]  Adrian Wiestner,et al.  ZAP-70 expression and prognosis in chronic lymphocytic leukaemia , 2004, The Lancet.

[27]  Adrian Wiestner,et al.  ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. , 2003, Blood.

[28]  Emili Montserrat,et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. , 2003, The New England journal of medicine.

[29]  G. Guida,et al.  The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. , 2003, Blood.

[30]  Axel Benner,et al.  Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. , 2002, Blood.

[31]  D. Oscier,et al.  Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. , 2002, Blood.

[32]  C. Bloomfield,et al.  Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). , 2002, Blood.

[33]  D. Oscier,et al.  CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. , 2002, Blood.

[34]  J. Dürig,et al.  CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia , 2002, Leukemia.

[35]  G. Capelli,et al.  Clinical significance of CD38 expression in chronic lymphocytic leukemia. , 2001, Blood.

[36]  Riccardo Dalla-Favera,et al.  Mechanisms of chromosomal translocations in B cell lymphomas , 2001, Oncogene.

[37]  K. Do,et al.  CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. , 2001, Blood.

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

[39]  T J Hamblin,et al.  Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. , 1999, Blood.

[40]  N. Chiorazzi,et al.  Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. , 1999, Blood.

[41]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[42]  F. Mancini,et al.  p53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis. , 1998, Blood.

[43]  F. Mancini,et al.  p 53 Expression in B-Cell Chronic Lymphocytic Leukemia : A Marker of Disease Progression and Poor Prognosis , 1998 .

[44]  M. Grever,et al.  National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. , 1996, Blood.

[45]  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.

[46]  B. Quesnel,et al.  p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. , 1994, Blood.

[47]  S. Knuutila,et al.  Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. , 1990, The New England journal of medicine.

[48]  Y. Nakamura,et al.  Allelotype of colorectal carcinomas. , 1989, Science.

[49]  Mark J. Thomas,et al.  A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis , 1981, Cancer.

[50]  D C Case,et al.  Clinical staging of chronic lymphocytic leukemia. , 1977, The Journal of the Maine Medical Association.