PMC:5003446 / 35605-50760 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5003446","sourcedb":"PMC","sourceid":"5003446","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5003446","text":"9. Mature B-Cell Lymphoproliferative Disorder\nMature B-cell neoplasms account for over 90% lymphomas, with the most common types being diffuse large B-cell lymphoma and follicular lymphoma. Diffuse large B-cell lymphoma (DLBCL) is composed of large neoplastic B-cells and genetically heterogeneous. Based on gene expression profiles, DLBCL can be further classified into germinal center B-cell like (GCB) type with good prognosis and activated B-cell like (ABC) type with poor prognosis. Scholtysik et al. [81] applied 250K SNP array on 148 cases of DLBCL and found recurrent genomic gains in 24 regions and recurrent genomic losses in 38 regions, with a median of 19 imbalances per case in GCB-DLBCL and 25 per case in ABC-DLBCL. A number of genetic alterations showed different frequencies in GCB and ABC-DLBCL, such as gains of HDAC7A on chromosome 12 predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 on chromosome 6 predominantly in ABC-DLBCL (35%), suggesting different pathways to lymphomagenesis in the two subtypes of DLBCL. Two new potential tumor suppressor genes CASP3 and IL5RA were identified in the analysis and showed no somatic mutations, suggesting a haploinsufficiency effect of the genes. Another study showed high frequency of LOH over chromosomal region 11p11.2 harboring the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ), which regulates a number of survival pathways [82]. The combination of SNP array and whole exome/whole transcriptome sequencing was especially productive and identified ARID1B, ROBO2, and MRS1 as potential tumor suppressor genes and KLHL6, IL31, and LRP1 as oncogenes in DLBCL [83]. The impact of genomic alterations on clinical course was studied by 250 SNP array in 124 patients treated with R-CHOP [84]. 20 recurrent genetic lesions were shown to have an impact on the clinical course, in which loss of 8p23.1 had the strongest statistical significance. In this study, five clusters of DLBCL showed distinct genetic profiles, clinical features, and outcomes.\nFollicular lymphoma (FL) is a mature B-cell lymphoma composed of malignant germinal center B-cells with some cases eventually transforming to diffuse large B-cell lymphoma. Early study with 10K SNP array on 26 cases of FL revealed recurrent aUDP on 6p, 9p, 12q, and 17p [85]. Homozygosity of 9p and 17p were found predominantly in transformed FL with homozygosity of pre-existing mutation of either CDKN2A or TP53 identified in a subset of cases. Interestingly, 10 cases showed chromosomal regions of homozygosity in FL that were absent in the subsequent transformed FL, suggesting the transformed FL derived from a common malignant precursor but not from step-wise clonal evolution of the preceding FL, at least in some cases [85]. The prognostic significance of aUPD was investigated in 185 cases of FL by 10K SNP array [86]. This study found genetic abnormalities in 65% cases, and more than three abnormalities were associated with inferior overall survival. Recurrent aUPD were detected on 6p, 16p, 12q, 1p36, 10q, and 6q, which were confirmed by other studies [87,88]. O’Shea et al. [86] showed that aUPD on 1p36 was correlated with shorter overall survival on multivariate analysis, and aUPD on 16p predicted transformation and poorer progression free survival. Somatic mutations of TNFRSF14 gene was identified by exon sequencing of the minimum region of deletion of ∼97 kb within 1p36.32, and TNFRSF14 mutations and 1p36 deletions were associated with inferior overall survival and disease specific survival after adjustment for the International Prognostic Index [89]. Individual genes including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways, were implicated by SNP array analysis in FL [87]. FL is characterized by t(14;18)(q32;q21) with IGH/BCL2 fusion, but a small subset of cases of FL is negative for t(14;18). The genetic profiles of t(14;18) positive and negative FL were compared by SNP array, and showed that gains/amplifications of the BCL2 gene locus at 18q were only present in the t(14;18)-positive FL [90].\nChronic lymphocytic leukemia is the most common leukemia in adults, and characterized by proliferation of small mature lymphoid cells in the peripheral blood, bone marrow, spleen and lymph nodes. Risk stratification based on FISH findings are routinely performed clinically. Early studies with 10 K and 50 K Affymetrix SNP arrays showed chromosomal imbalances in 65.6% and 82% cases, respectively, including UPD in 20% cases [91,92]. The cytogenetic changes commonly identified by FISH studies including trisomy 12, deletions of TP53 (17p13), ATM (11q22), and 13q14 were readily identified by SNP arrays. SNP arrays found a total of 45 CNAs in 45% cases excluding the four common cytogenetic changes identifiable by FISH [92]. High resolution Affymetrix SNP array 6.0 study on 353 samples of chronic lymphocytic leukemia (CLL) showed similar findings [93], with CN-LOH in 6% of CLL cases, most frequently on 13q, 17p, and 11q. Minimally-deleted regions were identified on 13q14 to the DLEU1 and DLEU2 genes, 11q22.3 to ATM, 2p16.1-2p15 to a 1.9-Mb fragment containing nine genes, and 8q24.21 to a 486 kb region proximal to the MYC locus. Breakpoint cluster regions flanking 13q deletions were found. A 3.5-Mb gain at 2p16 harboring REL and BCL11A oncogenes and deletion at 6q21 that involved the AIM1 gene were identified in a subset of cases [91,92], suggesting involvement of these genes in the pathogenesis of CLL. UPD was detected in 7% cases, with 50% involving whole chromosome 13 resulting in homozygous deletion of micro-RNA-15a (miR-15a)/miR-16-1 [92], which was confirmed by another study [94]. The genomic complexity identified by SNP array was an independent risk factor for aggressive CLL and short survival on multivariate analysis [94,95,96,97]. Large genomic aberrations identified by SNP array but not covered by the standard FISH panel was found to be an independent prognosticator of a shorter time to first treatment in CLL, by multivariate analysis [98]. Clonal evolution was shown to developed in 33% patients with unmutated IGHV, and in 16% treated patients with mutated IGHV, and included known recurrent aberrations such as del(13q) [94]. Analysis of clonal diversity by SNP array for genomic alterations and mosaic distribution of clones was also shown to be predictive of disease progression [99]. Del13q14 is the most frequent cytogenetic abnormality in CLL and associated with good prognosis. Ouillette et al. [100] showed that del13q14 was heterogeneous and composed of multiple subtypes, with deletion of RB or the miR15a/miR16 loci as anatomic landmarks. Large (type II) 13q14 deletions spanning the RB gene were associated with elevated genomic complexity, accelerated clinical course and short survival [101]. Similarly a separate study was able to classify CLL with del13q14 into two separate clusters characterized by short/biallelic deletion with loss of the miR-15a/16-1 versus wide/monoallelic 13q14 deletions [102]. Therefore, despite the established good prognosis of del13q14 by FISH, SNP arrays are clinically useful to identify a subset of cases with del13q14 that has poor prognosis. SNP arrays were shown to be able to supplement FISH studies with unusual signal patterns [103].\nMantle cell lymphoma is an aggressive B-cell lymphoma characterized by IGH/CCND1 translocation resulting in overexpression of cyclin D1. A large numbers of genomic abnormalities have been identified through metaphase cytogenetics and comparative genomic hybridization in addition to the characteristic t(11;14)(q13;q32). With 250K SNP array, Kawamata et al. [104] confirmed the presence of known genetic alterations, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53 in 33 samples of MCL. A duplication/amplification at 13q involving oncogenic microRNA, miR17-92, other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q), and a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD were identified by the SNP array. To identify the target genes in the genomic lesions, Beà et al. [105] combined SNP array and gene expression profiling and detected high number of partial UPDs with UPD 17p one of the most common associated with TP53 gene inactivation. 4 known tumor suppressor genes (CDKN2C, BCL2L11, CDKN2A, and RB1) and six new genes (FAF1, MAP2, SP100, MOBKL2B, ZNF280A, and PRAME) were identified in homozygous deletions. The most recurrent amplifications were at 11q13.3–q13.5, 13q31.3, and 18q21.33, targeting CCND1, C13orf25, and BCL2, which may be important for the lymphomogenesis of MCL.\nMarginal zone lymphoma is a diverse group of B-cell lymphoma derived from post-germinal center B-cells. SNP array studies in this group of lymphoma are limited. Flossbach et al. [106] examined a series of marginal zone B-cell lymphomas of the gastrointestinal tract including ones with large cell transformation by SNP array. They found increase of genomic complexity with lymphoma progression to large cell lymphoma. Gains of protooncogenes such as REL, BCL11A, ETS1, PTPN1, PTEN, and KRAS were identified exclusively in the large cell variants. Copy numbers of ADAM3A, SCAPER and SIRPB1 were also associated with progression from small to large cell lymphoma. The gene for tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), a negative regulator of NF-κB was found to be deleted at chromosomal region 6q23 in a small subset of marginal zone lymphomas by SNP array analysis [107]. In ocular adnexal MALT lymphoma, one study showed CNAs in approximately 70% cases and UPD detected on 6q (14%) and 3q (10%) [108]. The UPD on 6q likely involves the A20 gene. In this study, chromosomal gains were most commonly trisomy 3 (31%), trisomy 18 (17%), and 6p and 21q (14%), and the most frequent copy neutral (CN) loss regions were 6q and 9p (7%). Importantly, CNAs were not detected in reactive lymphoid hyperplasia, suggesting that SNP may be useful in difficult cases for diagnostic purpose.\nBurkitt lymphoma (BL) is an aggressive B-cell lymphoma mainly in pediatric patients and characterized cytogenetically by t(8;14)(q24;q32) involving the MYC gene. Illumina 1M SNP array was applied to 20 cases of BL to identify additional genomic lesions in addition to t(8;14)(q24;q32) [109]. Genomic imbalances were found in 95% cases by SNP array, including recurrent losses of 6q14.1–q22.33, 9p21.3, and 13q14.2–q14.3, gains of 1q23.3–q31.3, chromosome 7, 13q31.3, and partial UPD for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. These genetic alterations resulted in deletion of CDKN2A and TP53 genes, and gains/losses of other genes including MIR17HG and E2F2K that are involved in the MYC pathway, suggesting dysregulation of the MYC pathway by 8q24/MYC translocation or secondary genomic alterations are essential for development of Burkitt lymphoma.\nHairy cell leukemia (HCL) is an indolent B-cell neoplasm with “hairy cells” in the peripheral blood and bone marrow aspirates, and characteristic BRAF V600E mutation. With current therapy, patients with HCL have an excellent prognosis and near normal life span. HCL was found to have a remarkably stable genome by a 250K SNP array analysis [110]. With high resolution SNP Array 6.0, Rinaldi et al. [111] confirmed this finding. In this study, the 19 cases of HCL showed an extremely low numbers of CNAs with only two heterozygous losses detected (11%). These studies indicate very limited genetic damages in HCL, which may partly explain the excellent treatment response in current therapy.\nMultiple myeloma (MM) is a neoplasm of terminally differentiation B-cells (plasma cells) characterized by multisystem damage and presence of M-Spike in the peripheral blood. In a study of 30 samples of patients with newly diagnosed MM by a 50K SNP array, genomic alterations at 1p, 1q, 6q, 8p, 13, and 16q were most frequent [112]. Multiple regions of UPD were identified for the first time and were found to be interspersed throughout the genome, with a median of three UPD per sample (range, 0–19). These findings were largely confirmed by Agnelli et al. [113] in analyzing 41 cases of MM and four cases of plasma cell leukemia. Using unsupervised clustering methods five main groups of genetic imbalances were identified and showed strict correlation with transcriptional expression: cluster I with hyperdiploidy, particularly trisomy 11; cluster II with no or limited alterations; cluster III with 1q gain and chromosome 13 deletion; cluster IV with deletions of 1p, 13, 14, plus deletions of 8p and 22; and cluster V with near-tetraploidy. In an effort to address the prognostic significance of genetic lesions detected by high resolution SNP array, Avet-Loiseau et al. [114] showed deletions and amplifications in 98% of patients with MM. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were frequently associated with adverse prognosis, and recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 was associated with a favorable prognosis. Amp(1q23.3), amp(5q31.3), and del(12p13.31) retained independent prognostic value in multivariate analysis. Del(12p13.31) alone, or amp(5q31.3) and del(12p13.31), and high Sβ2M predicted a very poor prognosis. The prognostic significance of 1q amplification was confirmed by two other groups even after removing cases with the most adverse cytogenetic factors such as translocations involving FGFR3/MMSET, MAF, and MAFB, and del17p [115,116]. Walker et al. [115] identified UPD on 1q (8%), 16q (9%), and X (20%), that was associated with regions of gain and loss. Kamada et al. [116] showed accumulation of deletions and UPD at 22q12.1 associated with poor prognosis in hyperdiploid MM. With a 500K SNP array, Jenner et al. [117] identified LOH at 16q involving CYLD, a negative regulator of the NF-κB pathway, and WWOX, a tumor suppressor involved in apoptosis, that were independently associated with poor prognosis in MM. Multiple myeloma nowadays is typically treated with hypomethylating agent, bortezomib plus melphalan and prednisone. Kim et al. [118] showed that increasing genomic complexity identified by SNP arrays correlated with the outcome of the bortezomib plus melphalan and prednisone therapy. Patients with deletion of 1p and gain of 3q did not achieve very good partial response, while complex karyotype and gain of 3q were associated with progressive disease after therapy. Finally, López-Corral et al. [119] showed progressive increase in the incidence of CNAs from precursor monoclonal gammopathy of undetermined significance (MGUS) to MM. Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q, and 21q along with deletions of 1p, 16q, and 22q were significantly less frequent in MGUS than in MM. The frequency of UPD was higher in active MM than in the asymptomatic MM. As expected, the increasing genomic complexity from MGUS to MM is consistent with acquisition of additional genomic lesions as essential pathway to the progression from MGUS to 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