PMC:4996401 / 5871-15120 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4996401","sourcedb":"PMC","sourceid":"4996401","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4996401","text":"3.1. Diffuse Large B Cell Lymphoma\nDiffuse large B-cell lymphoma (DLBCL) is the most frequent NHL subtype, accounting for about 30% of all lymphoma cases worldwide. Although overall presenting as a unique entity, with the usage of gene expression profiling, it turned out that DLBCL is constituted by at least two distinct subtypes: germinal center B-cell like (GCB-DLBCL) and activated B-cell like (ABC-DLBCL) [2]. Furthermore, a third group of DLBCL cases exists, which have been defined as “gray zone”, which are not classifiable as either ABD or GCB subtypes [35].\nIn 2003, Wessendorf et al. [36] first demonstrated that increasing sensitivity of cytogenetic analysis by matrix comparative genomic hybridization (M-CGH) could allow to detect previously uncovered lesions in DLBCL and other aggressive lymphoma specimens. Among others, the authors identified small amplifications affecting genes involved in lymphoma pathogenesis such as BCL2, REL, CCND1, CCND2, JAK2, FGF4 and MDM2. This basic evidence prompted further research toward more and more sensitive tools. Since then, in fact, several studies have been carried out using SNP arrays alone or in combination with other methods to uncover unidentified genes involved in DLBCL (Table 1) [37,38,39,40,41,42,43,44,45,46,47,48]. While some features, e.g., gains on chromosome 7, are common between the two subtypes, many others such as gains on chromosomes 1, 7, 12, 3, 18, 2, 19 and 13 and losses on chromosomes 9, 6, 7, 15 and 17 might affect the differences between the two subtypes. Among the affected genes by gains, REL, BCL2, BCL11A and mir-17, and among the affected genes by losses PTEN, PRDM1, TP53, TNFAIP3, JAK2, BACH2, CASP8AP2, HDAC7A and FAS are worth to mention [37,38,39,40,41,42,43,44,45,46,47,48].\nAs far as the differences between the two subtypes of DLBCL are concerned, Scholtysi et al. [43] conducted a study mainly focused on the matter, analyzing 148 primary tumors (including 79 GCB-DLBCL, 49 ABC-DLBCL and 20 unclassified cases) [42,43]. Collectively, they found 24 and 38 regions of recurrent gains and losses and 38 regions of recurrent genomic losses, respectively, averaging 25 and 19 imbalances per case for ABC-DLBCL and GCB-DLBCL, respectively. Among them, a recurrent deletion was found in 19p13.3 in several primary cases, which included two members of Tumor Necrosis Factor superfamily, namely TNFSF7 and TNFSF9. Furthermore, they identified several copy number variations with substantially differential frequencies among the two subtypes of DLBCL. For example, a loss on chromosome 9 (a region covering tumor suppressor genes CDKN2A and CDKN2B) was found in 46.9% of ABC-DLBCL cases, while the occurrence of this loss in GCB-DLBCLs was only 12.7%. Other examples include gain on chromosome 2 (including REL and BCL11A genes) with an occurrence rate of 10.2% and 30.4% for ABC- and GCB-DLBCL, respectively, gains of HDAC7A on chromosome 12 mainly observed in GCB-DLBCL (38% of cases as compared to 14.3% in ABC-DLBCL) and predominant losses of BACH2 and CASP8AP2 ABC-DLBCL (34.7% vs. 20.3% in GCB subtype) [42,43].\nmicroarrays-04-00551-t001_Table 1 Table 1 The most important recurrent genetic aberrations in diffuse large B-cell lymphoma (DLBCL), as discussed in the text. Very recently, Dias et al. [47] used an intercross of public datasets from three different platform types (i.e., SNP array, CGH array and Gene expression Profiling) to analyze 392 DLBCL samples, looking for the CNV associated with the differential gene expression levels. Among the abnormal genomic regions identified by them, 32 turned out to be overlapped between at least two datasets. Based on the data, they defined 36 minimal common regions (MCR), several of which overlapped with peaks defined by GISTIC program, among which gains on 2p16.3–p14 (REL) and 9q34.11–q34.3 (NOTCH1) and losses on 1p13.2–p12 (CD58), 6p12.3–q27 (TNFAIP3), 9p24.3–p21.1 (JAK2, CDKN2A), 10q23.2–23.32 (FAS) and 19p13.3–p13.2 (CD70) can be mentioned [47].\nAs expected, SNP arrays have helped to define better the possible role of human genes in malignancies. For example, a locus in chromosomal location 15q15 encoding for p53-Binding protein 1 (53BP1), the protein product of which has a major role in DNA double strand break repair, was reported to be a subject of single copy loss in 9 out of 63 (14.5%) cases of DLBCL, as indicated by Takeyama et al. [44]. Interestingly, the same authors found a significant decrease in the gene expression level of 53BPI in the related tumor cases, indicating for the first time a possible role of this gene in human malignancies. Of note, this was the first report of such a role in human tumors [44]. Furthermore, although analyzing a limited number of DLBCL cases (n = 18), by combining SNP array technology and transcriptome profiling, Green et al. [40] found genetic lesions that significantly enriched for apoptosis and the mitogen activated protein kinase pathways. They were able to recognize two recurrent amplifications in DLBCL primary tumors, including 12p13.33 targeting FOXM1 and 12q13.13, targeting MAP3K12. The authors argued the possible role of FOXM1 in non-hodgkin lymphomagenesis, demonstrating its possible association an increased MYC oncogenic signaling signature [40]. In another study on 242 DLBCL cases, Conde et al. [48] found a duplication for the chromosomal region 11q25 in 6.2% of cases. Interestingly, this region encodes for a long non-coding RNA (LOC283177), which further highlights the accumulating evidences for the role of this family of RNAs in human diseases.\nRemarkably, some CNV patterns appeared significantly related with treatment response (when R-CHOP was considered as therapy) and overall survival [38,41,45,49]. Specifically, first of all, based on a study on 203 samples, the LMPP (Leukemia/Lymphoma Molecular Profiling Project) provided the genetic evidence that ABC- and GCB-DLBCL are distinct. In fact, they identified 272 recurrent chromosomal aberrations associated with gene expression alterations, 30 of which could efficiently separate the two DLBCL subtypes (p \u003c 0.006) [45]. Among them, an amplicon on chromosome 19 was detected in 26% of ABC-DLBCLs but in only 3% of GCB-DLBCLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor and which was later on functionally related the pathogenesis of ABC-DLBCL. Similarly, Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 (leading to the over-expression of FOXP1) also occurred almost exclusively in ABC-DLBCLs and were associated with inferior outcome within this subtype. By contrast, in GCB-DLBCL, amplification of the oncogenic miR-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but were not observed in the ABC-subtype [45].\nSubsequently, Scandurra et al. [41] studied 166 primary samples and identified 20 recurrent genetic lesions that showed an impact on the clinical course. Among them, lesions with the strongest association with a worse outcome were deletions affecting the short arm of chromosome 8, including del(8p23.1) (p = 0.002), del(8p) (p = 0.01), and del(8p23.1–21.2) (p = 0.012). The loss of genomic material at 8p23.1 also appeared to be associated with additional aberrations, such as 17p- and 15q-. Overall, seven pathways appeared to be significantly enriched within the loci affected by CNV associated with survival: regulation of autophagy, natural killer cell-mediated cytotoxicity, antigen processing and presentation, Toll-like receptor signaling pathway, JAK-STAT signaling pathway, apoptosis and cytokine-cytokine receptor interaction. Finally, unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics (e.g., bone marrow involvement) and outcomes [41]. In another study performed by the GELA group, it was found that losses of TP53 and CDKN2A, observed in 8% and 35% of 114 DLBCL patients analyzed, respectively, were significantly associated with a shorter survival after R-CHOP treatment, independently of the International Prognostic Index [49]. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an ABC-profile and showed a specific gene expression signature, characterized by deregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses [49]. More recently, Monti et al. [38] studies 180 primary cases and showed that DLBCL cases showed either multiple complementary alterations of TP53 and cell cycle components or largely lacked such lesions. DLBCLs with TP53 and cell cycle pathway copy number abnormalities had decreased abundance of p53 transcriptional targets and increased expression of E2F target genes as well as increased Ki67 proliferation marker and poor clinical outcome [38].\nFinally, some frequent regions showing LOH, including 11p11.2 have been identified in DLBCL cases. The latter which affects PTPRJ, was reported in 38% (16/42) of primary DLBCLs, indicating the LOH (and possible subsequent inactivation) of PTPRJ as a recurring event in NHLs [46].","divisions":[{"label":"Title","span":{"begin":0,"end":34}},{"label":"Table 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