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Blood, 1 January 2007, Vol. 109, No. 1, pp. 271-280.
Prepublished online as a Blood First Edition Paper on September 7, 2006; DOI 10.1182/blood-2006-06-026500.
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NEOPLASIA
Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas
Cinta Mestre-Escorihuela1,
Fanny Rubio-Moscardo1,
Jose A. Richter1,
Reiner Siebert2,
Joan Climent1,
Vicente Fresquet1,
Elena Beltran1,
Xabier Agirre1,
Isabel Marugan3,
Miguel Marín3,
Andreas Rosenwald4,
Kei-ji Sugimoto5,
Luise M. Wheat5,
E. Loraine Karran5,
Juan F. García6,
Lydia Sanchez6,
Felipe Prosper1,
Louis M. Staudt7,
Daniel Pinkel8,
Martin J. S. Dyer5, and
Jose A. Martinez-Climent1,
1 Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Pamplona, Spain;
2 Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany;
3 Department of Hematology and Medical Oncology, Hospital Clínico, University of Valencia, Valencia, Spain;
4 Department of Pathology, University of Würzburg, Würzburg, Germany;
5 Medical Research Council (MRC) Toxicology Unit, University of Leicester, United Kingdom;
6 Molecular Pathology Program, National Center for Oncology Research (CNIO), Madrid, Spain;
7 National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD; and
8 Cancer Research Institute, University of California San Francisco, CA
Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.
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