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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.
 Previous Article | Next Article 
Submitted June 2, 2006
Accepted August 16, 2006
Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas
Cinta Mestre-Escorihuela, Fanny Rubio-Moscardo, Jose A Richter, Reiner Siebert, Joan Climent, Vicente Fresquet, Elena Beltran, Xabier Agirre, Isabel Marugan, Miguel Marin, Andreas Rosenwald, Kei-Ji Sugimoto, Luise M Wheat, E Loraine Karran, Juan F Garcia, Lydia Sanchez, Felipe Prosper, Louis M Staudt, Daniel Pinkel, Martin JS Dyer, and Jose A Martinez-Climent*
Center for Applied Medical Research, Division of Oncology, University of Navarra, Pamplona, Spain
Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany
Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Spain
Department of Pathology, University of Wurzburg, Germany
MRC Toxicology Unit, University of Leicester, UK
Molecular Pathology Program, National Center for Oncology Research (CNIO, Madrid, Spain)
National Cancer Institute, NIH, Bethesda, MD, USA
Cancer Research Institute, University of California San Francisco, CA, USA
Center for Applied Medical Research, University of Navarra, Pamplona, Spain
* Corresponding author; email: jamcliment{at}unav.es.
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 twenty homozygous deletions at seven 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 pro-apoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the pro-apoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma and the INK4c/P18 was silenced by bi-allelic 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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