Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.
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.
Mestre-Escorihuela
Cinta
C
Center for Applied Medical Research (CIMA), University of Navarra, Avda Pio XII, 55, Pamplona 31008, Spain. jamcliment@unav.es.
Rubio-Moscardo
Fanny
F
Richter
Jose A
JA
Siebert
Reiner
R
Climent
Joan
J
Fresquet
Vicente
V
Beltran
Elena
E
Agirre
Xabier
X
Marugan
Isabel
I
Marín
Miguel
M
Rosenwald
Andreas
A
Sugimoto
Kei-Ji
KJ
Wheat
Luise M
LM
Karran
E Loraine
EL
García
Juan F
JF
Sanchez
Lydia
L
Prosper
Felipe
F
Staudt
Louis M
LM
Pinkel
Daniel
D
Dyer
Martin J S
MJ
Martinez-Climent
Jose A
JA
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016601:RNA-Binding Proteins; D017384:Sequence Deletion; D058305:Sorting Nexins; D014157:Transcription Factors / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C493971:CDKN2C protein, human; D002352:Carrier Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; C118738:LITAF protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; C517049:SNX25 protein, human; C490755:SORBS2 protein, human; D058305:Sorting Nexins; D014157:Transcription Factors; D033921:Vesicular Transport Proteins