Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances.

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model-based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q-, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.

[1]  S. Tsuzuki,et al.  TNFAIP3 is the target gene of chromosome band 6q23.3‐q24.1 loss in ocular adnexal marginal zone B cell lymphoma , 2008, Genes, chromosomes & cancer.

[2]  B. Emanuel,et al.  From microscopes to microarrays: dissecting recurrent chromosomal rearrangements , 2007, Nature Reviews Genetics.

[3]  A. Advani,et al.  Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma , 2007, Bone Marrow Transplantation.

[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]  H. Tagawa,et al.  Genome‐wide array‐based comparative genomic hybridization of ocular marginal zone B cell lymphoma: Comparison with pulmonary and nodal marginal zone B cell lymphoma , 2007, Genes, chromosomes & cancer.

[6]  T. Lister,et al.  Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma , 2007, Leukemia.

[7]  C. Mahaffey,et al.  Complex Seizure Disorder Caused by Brunol4 Deficiency in Mice , 2007, PLoS genetics.

[8]  Kevin P. Murphy,et al.  Modeling recurrent DNA copy number alterations in array CGH data , 2007, ISMB/ECCB.

[9]  Jan Delabie,et al.  Transformation of follicular lymphoma to diffuse large B‐cell lymphoma proceeds by distinct oncogenic mechanisms , 2007, British journal of haematology.

[10]  C. Larsson,et al.  Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma , 2007, Modern Pathology.

[11]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[12]  Carolyn J. Brown,et al.  A comprehensive analysis of common copy-number variations in the human genome. , 2007, American journal of human genetics.

[13]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[14]  Kevin P. Murphy,et al.  Integrating copy number polymorphisms into array CGH analysis using a robust HMM , 2006, ISMB.

[15]  T. Stokke,et al.  Translocation t(14;18) and gain of chromosome 18/BCL2: effects on BCL2 expression and apoptosis in B-cell non-Hodgkin's lymphomas , 2005, Leukemia.

[16]  Rabab Kreidieh Ward,et al.  BMC Bioinformatics Methodology article A stepwise framework for the normalization of array CGH data , 2005 .

[17]  M. Calaminici,et al.  A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma , 2005, Leukemia.

[18]  Calum MacAulay,et al.  High-resolution array CGH increases heterogeneity tolerance in the analysis of clinical samples. , 2005, Genomics.

[19]  S. Loibl,et al.  Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  P. Solal-Céligny,et al.  Follicular lymphoma international prognostic index , 2006, Blood.

[21]  H. Tagawa,et al.  Comparison of genetic aberrations in CD10+ diffused large B‐cell lymphoma and follicular lymphoma by comparative genomic hybridization and tissue‐fluorescence in situ hybridization , 2004, Cancer science.

[22]  Randy D Gascoyne,et al.  Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes. , 2004, Human molecular genetics.

[23]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[24]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[25]  D. Wallach.  Faculty Opinions recommendation of De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. , 2004 .

[26]  S. Swerdlow,et al.  Utility of routine classical cytogenetic studies in the evaluation of suspected lymphomas: results of 279 consecutive lymph node/extranodal tissue biopsies. , 2004, American journal of clinical pathology.

[27]  R. Gascoyne,et al.  Delineation of a minimal region of deletion at 6q16.3 in follicular lymphoma and construction of a bacterial artificial chromosome contig spanning a 6‐megabase region of 6q16–q21 , 2004, Genes, chromosomes & cancer.

[28]  S. Verstovsek,et al.  Nuclear factor‐KappaB modulation as a therapeutic approach in hematologic malignancies , 2004, Cancer.

[29]  Mattias Höglund,et al.  Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas , 2004, Genes, chromosomes & cancer.

[30]  Rebecca A. Ihrie,et al.  Perp-etrating p53-Dependent Apoptosis , 2004, Cell cycle.

[31]  Bradley P. Coe,et al.  A tiling resolution DNA microarray with complete coverage of the human genome , 2004, Nature Genetics.

[32]  Calum MacAulay,et al.  SeeGH – A software tool for visualization of whole genome array comparative genomic hybridization data , 2004, BMC Bioinformatics.

[33]  R. Gascoyne,et al.  Multicolour fluorescence in situ hybridization analysis of t(14;18)‐positive follicular lymphoma and correlation with gene expression data and clinical outcome , 2003, British journal of haematology.

[34]  E. Haralambieva,et al.  Identification of chromosomal copy number changes associated with transformation of follicular lymphoma to diffuse large B-cell lymphoma. , 2003, Human pathology.

[35]  D. Bonthron,et al.  Detection by fluorescence in situ hybridization of microdeletions at 1p36 in lymphomas, unidentified on cytogenetic analysis. , 2003, Cancer genetics and cytogenetics.

[36]  R. Siebert,et al.  Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  David Botstein,et al.  Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Gascoyne,et al.  Uncovering novel inter‐ and intrachromosomal chromosome 1 aberrations in follicular lymphomas by using an innovative multicolor banding technique , 2002, Genes, chromosomes & cancer.

[39]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[40]  A. Al-Katib,et al.  Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant. , 2001, Cancer genetics and cytogenetics.

[41]  R. Gascoyne,et al.  Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18) , 2001, Genes, chromosomes & cancer.

[42]  P. Lorigan,et al.  Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma , 2001, British Journal of Cancer.

[43]  Clara D. Bloomfield,et al.  The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting--Airlie House, Virginia, November, 1997. , 2000, The hematology journal : the official journal of the European Haematology Association.

[44]  G Flandrin,et al.  The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  A. Rosenwald,et al.  Deletions in the Long Arm of Chromosome 10 in Lymphomas With t(14;18): A Pathogenetic Role of the Tumor Suppressor Genes PTEN/MMAC1 and MXI1? , 1998 .

[46]  A. Rosenwald,et al.  Deletions in the long arm of chromosome 10 in lymphomas with t(14;18): a pathogenetic role of the tumor supressor genes PTEN/MMAC1 and MXI1? , 1998, Blood.

[47]  R. Bataille,et al.  Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas , 1997, British journal of haematology.

[48]  R. Siebert,et al.  High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma. , 1996, Blood.

[49]  R. Mertelsmann,et al.  BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  D. Jong,et al.  Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. , 1995, Blood.

[51]  Annick,et al.  Prognostic value of chromosomal abnormalities in follicular lymphoma. , 1994, Blood.

[52]  T. McDonnell,et al.  Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18) , 1991, Nature.

[53]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[54]  S. Korsmeyer,et al.  Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. , 1987, The Journal of clinical investigation.

[55]  M. Oken,et al.  Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. , 1987, The New England journal of medicine.

[56]  P. Nowell,et al.  Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. , 1984, Science.