Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways.
Primary diffuse large B-cell lymphomas of different immune-privileged sites (IP-DLBCLs) share many clinical and biological features, such as a relatively poor prognosis, preferential dissemination to other immune-privileged sites, and deletion of the HLA region, which suggests that IP-DLBCL represents a separate entity. To further investigate the nature of IP-DLBCL, we investigated site-specific genomic aberrations in 16 testicular, nine central nervous system (CNS), and 15 nodal DLBCLs using array CGH. We also determined minimal common regions of gain and loss. Using robust algorithms including multiple testing procedures and the ACE-it script, which is specifically designed for this task, the array CGH data were combined with gene expression data to explore pathways deregulated by chromosomal aberrations. Loss of 6p21.32-p25.3, including the HLA genes, was associated with both types of IP-DLBCL, whereas gain of 2p16.1-p25.3 was associated with nodal DLBCL. Gain of 12q15-q21.1 and 12q24.32-q24.33 was associated with CNS DLBCL and gain of 19q13.12-q13.43 with testicular DLBCL. Analysis of candidate genes in site-specific regions and minimal common regions revealed two major groups of genes: one involved in the immune response, including regulation of HLA expression, and the other involved in apoptosis, including the p53 pathway. Many of these genes were also involved in homozygous deletions or high-level gains. The presence of both shared and site-specific aberrations in CNS and testicular DLBCLs underlines the concept of IP-DLBCL but also indicates that IP-DLBCLs of the CNS and testis do not form a single entity. The observed aberrations emphasize the importance of the deregulation of anti-tumour immune response and apoptosis pathways.
Booman
M
M
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.booman@path.umcg.nl
Szuhai
K
K
Rosenwald
A
A
Hartmann
E
E
Kluin-Nelemans
Hc
H
de Jong
D
D
Schuuring
E
E
Kluin
Pm
P
D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000276:immunology; D002869:Chromosome Aberrations; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics / Q000276:immunology