High Resolution Array-CGH in Splenic Marginal Zone B-Cell Lymphoma: Correlation of Copy Number Imbalances with HCV Status and Prognostic Categories.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2620-2620
Author(s):  
Francesca Novara ◽  
Luca Arcaini ◽  
Michele Merli ◽  
Francesco Passamonti ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Copy Number ◽  
Marginal Zone ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Mutational Status

Abstract In splenic marginal zone B-cell lymphoma (SMZL) no specific genetic alterations are known. Abnormalities of chromosome 7p and of p53 are reported as adverse prognostic factors. In a recent multicentre study (Arcaini et al Blood 2006), a prognostic model based on hemoglobin, albumin and LDH identified 3 risk categories. HCV infection was present in nearly 20% of patients (pts). At now, no data are available on genetic alterations in the HCV-positive subset of SMZL and in the different prognostic categories. The aims of the study were: a) to analyze copy number alterations (CNAs) by means of array comparative genomic hybridization (array-CGH) with a resolution of ∼100 kb; b) to compare CNAs in HCV-positive and HCV-negative pts; c) to identify potential genetic alterations related to the clinical features and to the prognostic categories. We analyzed marrow and blood samples from 34 pts with SMZL: 22 were HCV-negative (serology and HCV-RNA) and 12 were HCV-positive (genotype 2a/2c in 10 pts, genotype 1 in 2). DNA was extracted from bone marrow (16) and peripheral blood lymphocytes (18) and was hybridized with pooled blood lymphocyte reference DNA on Agilent’s 44K oligonucleotide microarray (kit 44B). Images and data were analyzed using Agilent’s Feature Extraction (v9.1) and CGH analytics (v3.4.27) softwares. Ten cases (4 HCV+ and 6 HCV-) did not show CNAs. A single alteration was present in 7 pts, 2 to 5 alterations in 11 and >5 in 6. All CNAs were detected in mosaicism (from 20% to 90%). A median of 5.6 (range 1 to 20) and 3.8 (range 1 to 13) CNAs were detected in HCV+ and in HCV- cases, respectively. The most frequent CNAs were hetereogeneous in size with the following common regions: losses of 1p36.21-p35.3 (3 pts), 7q31.1-q32.3 (7 pts), 8p21.3-p12 (6 pts), 13q14.2-q14.3 (6 pts), 14q32.12-q32.13 (4 pts) and 17pter-p12 (8 pts); gains of 3q21.1-q29 (5 pts), 12q13.1-q21.31 (5 pts), 17q24.1-qter (4 pts), Xpter-p11.23 (4pts). A homozygous 13q14.2 deletion, overlapping that found in CLL and including Rb1 gene, was found in one HCV- pt. The del(7)(q31.1-q32.3) was the more frequent and it ranges from 14,1Mb to 34Mb. No difference in number of CNAs and in specific common regions alterations was found between HCV+ and HCV- cases except for dup(X)(pter-p11.23) (p=0.01, 4 HCV+ pts and none HCV- pt). High-risk prognostic category was significantly associated with del(7)(q31.1-q32.3) (p=0.01) and del(17)(pter-p12) (p=0.02). Mutational status of immunoglobulin variable heavy-chain gene was related to del(7)(q31.1-q32.3) (p=0.04) and dup(12)(q13.1-q21.31) (p=0.03). The presence of villous lymphocytes was associated with del(1)(p36.21-p35.3) (p=0.02); del(8)(p21.3–p12) was related to an autoimmune background in the HCV+ subset (p=0.04). The number of CNAs was associated to leukemic disease (p=0.02) and to the presence of villous lymphocytes (p=0.04). In conclusion, array-CGH in SMZL does not show specific genetic abnormalities for pts with HCV-positive or HCV-negative SMZL. 7q and 17p deletions are significantly associated with the high-risk prognostic category, clinically and biologically identifying a group of pts with aggressive disease.

Splenic Marginal Zone Lymphoma Shows a Distinct Pattern of DNA Copy Number Aberrations That Correlates with Tumor Characteristics and Predicts Disease Outcome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2422-2422
Author(s):  
Jose A. Martinez-Climent ◽  
Cristina Robledo ◽  
Manuela Mollejo ◽  
Anton Parker ◽  
Juan L. Garcia ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Marginal Zone ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Genomic Aberrations ◽  
7Q Deletion

Abstract Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy whose diagnosis is based on lymphocyte morphology, immunophenotype and marrow and/or splenic histology. Unlike other lymphomas, there is not a common chromosomal translocation specific for SMZL, and genetic prognostic factors are poorly defined. To investigate the pattern of genomic aberrations in SMZL, we applied comparative genomic hybridization to BAC microarrays (array CGH) to a well characterized series of 75 SMZL specimens. We applied two different 1 Mb-resolution BAC arrays: UCSF HumArray 3.2 and a novel array CGH platform developed at Univ. of Salamanca. These arrays allowed us to detect DNA copy number changes across the genome with high accuracy in 67 of 75 patient samples. Data were compared with our previous array CGH studies of 170 samples from different B-cell lymphoma subgroups. FISH studies for IGH, IGK and IGL translocations and 7q deletion were performed on tissue microarrays in 24 cases. Of the 67 samples, 19 (28%) showed a normal genomic profile. The median number of genomic aberrations per tumor was 2.2 (1.3 gains and 0.9 losses), which was lower than the rates detected in other lymphoma subgroups (diffuse large cell lymphoma, 6.4; mantle cell lymphoma, 6; follicular lymphoma, 4.5) and comparable to MALT lymphomas (2 abnormalities per tumor). SMZL cells showed a genomic pattern characterized by gain of chromosomes 3q24-q29 (18%), 6p (9%), 12q (9%), and 18q (4%) and loss of 7q32 (34%), 8p21-p23 (13%), 17p13 (10%) at P53 locus and 6q21-q27 (9%). Notably, no alterations of the P16/ARF (9p21) or MYC loci (8q24) were detected. Correlation of array CGH data with conventional cytogenetics, FISH and LOH studies revealed a high concordance. Detailed mapping of 7q deletions delineated a consensus region of loss of 3 Mb in 7q32. This 7q deletion was almost exclusive to SMZL, being observed in only 5 of 170 non-SMZL B-cell lymphomas (p=0.0000001). Four cases presented IG-translocation. Mutation of IGH was observed in 62% and correlated with a complex karyotype (61 vs. 13%; p=0,0008) whereas unmutated IGH correlated with the deletion of 7q (56 vs. 23%; p=0,01). Among the various genomic abnormalities, only the deletion of 8p or the presence of a complex karyotype correlated with inferior overall survival (OS) (median OS, 58 vs. 110 months, p=0,004; and 60 vs. 105 months, p=0,01; respectively). In summary, array CGH has defined a pattern of genomic aberrations in SMZL that differs from other B-cell lymphoma subgroups and that may predict overall survival. Because the deletion of 7q32 is the most distinctive genetic marker in SMZL, the identification of a putative tumor suppressor gene inactivated within the region of deletion seems mandatory.

scholarly journals The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 143 (6) ◽  
pp. 520-528
Author(s):  
Yang Xia ◽  
Xinlian Zhang
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Novel Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, <i>MYC</i> translocations, <i>MYC</i> mutations, and increased gene copy number of <i>MYC</i>. Noteworthy, lone MYC overexpression or <i>MYC</i> translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of <i>MYC</i> together with <i>BCL2</i> or <i>BCL6</i>, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of <i>MYC</i> mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

scholarly journals Biological and Clinical Significance of PIM1 Genetic Alterations in Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3494-3494
Author(s):  
Xianhuo Wang ◽  
Yaxiao Lu ◽  
Yue Fei ◽  
Lanfang Li ◽  
Lihua Qiu ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Signaling Pathway ◽  
Risk Score ◽  
Validation Cohort ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Signature ◽  
Genetic Alterations ◽  
Large B Cell Lymphoma

Abstract Background: PIM1 is a somatic hypermutation gene in diffuse large B-cell lymphoma (DLBCL) and its inhibitors exhibit a great value in application in multiple types of lymphoma. Nevertheless, investigation on its genetic alterations, biological characteristics, clinical significance and response to drugs is still lacking. Methods: We integrated the genome sequencing (discovery cohort, n=162; validation cohort, n=1001) and transcriptome sequencing (discovery cohort, n=140; validation cohort, n=928) to capture more detailed insights into the potentially biological functions of PIM1 genetic alterations, and analyzed their relationship with biological characteristics and clinical value which provide a possibility for risk stratification and therapeutic exploitation for patients with DLBCL. Results: PIM1 mutations were identified in 28.4% of DLBCL patients and significantly correlated with higher IPI scores (P=0.013), disease relapse (P=0.031) and CNS and/or testis involvement (P=0.001), as well as inferior PFS (P=0.022) and OS (P=0.0022). Multivariate analysis revealed that PIM1 mutation status was an independent poor prognostic factor (HR=2.86; 95% CI, 1.40-5.84; P=0.004). The most frequent PIM1 mutation type was missense mutations (84.1%), followed by frameshift deletions and nonsense mutations. During the distribution of base substitutions, C &gt; T base substitution was predominant mutation type (54.4%), followed by C &gt;G transversion (29.3%). During different exons, exon 4 of PIM1 was most often mutated. PIM1 mutations significantly co-occurred with the mutations of SETD1B (P&lt;0.001) and CD79B (P=0.001), and was mutually exclusive to the SPEN mutation (P=0.024). We also explored the relationship between PIM1 mutations and genes distributed on previously reported signaling pathways in DLBCL and uncovered that mutations in MYD88 (P&lt;0.001) and PRDM1 (P&lt;0.001) involved in the NF-κB pathway were significantly enriched in the patients with PIM1 mutations. Unsurprisingly, patients with PIM1 mutations exhibited higher mutation frequencies in CD79B (P=0.001) involved in BCR pathway. PIM1 mutations were involved in immunoglobulin-related immune response, complement activation, B cell mediated immunity, B cell activation, antigen binding, and cytokine activity, which contributed to the signaling pathways of tumor microenvironment (e.g. cytokine-cytokine receptor interaction, chemokine signaling pathway, IL-17 signaling pathway, TNF signaling pathway), JAK-STAT and NF-κB. By MCODE analysis, five significant modules were obtained from the protein-protein interaction (PPI) network. Finally, a PIM1 mutation-related gene signature consisting of some independent prognostic factors was developed. According to the risk score, patients with high-risk score exhibited significantly shorter OS (P=0.0016) and PFS (P&lt;0.001). The areas under the curve (AUCs) for the predictions of 1-, 3-, and 5-year OS were respectively 0.69, 0.70, and 0.72, suggesting that the risk score based on the PIM1 mutation-related gene signature had satisfactory sensitivity and specificity. We further found that compared to patients with low-risk score, patients with high-risk score had higher sensitivity to some drugs of targeting the immune microenvironment, including TGFβ receptor inhibitors SB525334 (P&lt;0.0001) and SB505124 (P&lt;0.0001) and immunomodulator Lenalidomide (P=0.041), as well as NF-κB inhibitors Parthenolide (P&lt;0.0001) and TPCA-1 (P&lt;0.0001) and JAK inhibitors Ruxolitinib (P=0.014) and TG101348 (P=0.0053), accompanying with significantly lower IC50 values. In addition, another common chemotherapeutic drug Gemcitabine was also predicted to be more sensitive for patients with high-risk score (P=0.047). Other targeted drugs such as Aurora kinase inhibitors VX-680 (P&lt;0.0001) and ZM-447439 (P=0.014), Bcl-2 inhibitors Obatoclax Mesylate (P=0.00036) and Navitoclax (P&lt;0.0001), and CDK inhibitors Roscovitine (P=0.0012), AT-7519 (P=0.0033), PHA-793887 (P&lt;0.0001) and THZ2-49 (P=0.0053) also exhibited higher drug sensitivity for patients with high-risk score. Conclusions: PIM1 mutations play a vital role in patient risk stratification and provide novel insights into therapeutic decision making for DLBCL patients with high-risk score. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma

Haematologica ◽  
2021 ◽  
Author(s):  
Man Chun John Ma ◽  
Saber Tadros ◽  
Alyssa Bouska ◽  
Tayla Heavican ◽  
Haopeng Yang ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Cross Sectional ◽  
Disease Etiology ◽  
Dna Copy Number Alterations

B-cell non-Hodgkin’s lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Identification of Target Gene at 2p15 Amplification in DLBCL Using Contig Array CGH.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4361-4361
Author(s):  
Noriko Fukuhara ◽  
Hiroyuki Tagawa ◽  
Yasuhiro Kameoka ◽  
Yumiko Kasugai ◽  
Sivasundaram Karnan ◽  
...  
Keyword(s):  
B Cell ◽  
Target Gene ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Comparative Genomic ◽  
Genomic Amplification ◽  
Large B Cell Lymphoma ◽  
A Genome ◽  
Large B Cell

Abstract Genomic amplification of the 2p arm has been identified as a recurrent alteration in classical Hodgkin lymphoma, follicular lymphoma, primary mediastinal large B cell lymphoma and diffuse large B-cell lymphoma (DLBCL). We previously reported that 2p15 was gained in 25 out of 100 DLBCL patients by use of a genome-wide array-comparative genomic hybridization (array-CGH). In DLBCL with 2p amplification, genomic co-amplification of REL and BCL11A has been observed. Recent studies suggest that REL amplification is infrequently associated with nuclear REL expression and NFkB activation. In an attempt to identify the target gene at 2p15 amplification, we made BAC contig array CGH glasses for 2p15 region with 33 BAC clones covering 4.5Mb, and found that seven samples of the DLBCL with 2p amplification displayed alterations. REL and BCL11A were located within majority of the gained regions. The minimal common region of amplification was mapped to 0.5 Mb and we found that this region did not include BCL11A. To investigate the relationship between genomic gains and gene expression, we performed real-time quantitative polymerase chain reaction (RQ-PCR) analysis. The results indicated that REL, rather than BCL11A, is the target of 2p15 alterations in DLBCL.

Non Hodgkin Lymphoma (NHL) Distribution and Clinical Characteristics in a Mexican Registry with High Frequency of T Cell NHL: A Descriptive Study on Behalf of Mexican Hematology Study Group (MHSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4407-4407
Author(s):  
Gregorio Ignacio ◽  
Francisco Tripp ◽  
Petty Rodríguez ◽  
Mario Martínez ◽  
Concepción Martínez ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
T Cell Lymphomas ◽  
Mantle Cell

Abstract Background: Among the NHL, B Cells NHL are more frequent than T Cells NHL (6%) as described in USA & European reports. The highest frequencies of T Cell NHL have been reported in Japan with 9% and India with 12%. In a Mexican retrospective study we found a T Cell NHL frequency of 13%. Objective: To corroborate the patterns and frequency of B and T cell lymphomas in Mexico. Methods: The registry of lymphoid neoplasms was created based on the WHO classification. The Lymphoma subtype analysis was prepared in two periods: retrospectively from 2002 to December 2005 and prospectively from January to December 2006. The data recorded were: age, sex, cell type (B o T), NHL frequency, primary site, stage and prognostic index (IPI and FLIPI). Results: In the first group 2375 Lymphomas were included: 2122 B Cell NHL (89.34%) and 253 T-cell lymphomas 253 (10.6%). B-cell NHL: gender 55.17% male and 44.66 female, median age of 55.21 years Age >60 years 45.7%; 62% III–IV stage. After applying the FLIPI index, the patients were divided into three risk groups: low (8.4% of cases), intermediate (81%), and high (10.6%). The distribution of patients in IPI risk groups was 15.7%, 76%, and 8.3% of cases classified as low, intermediate, and high risk The frequencies of B cell lymphoma were: 49% DLBCL, 15% Follicular Lymphoma, 5.35% CLL/SLL, 1.6% Mantle cell Lymphoma, 0.9% Follicular Center Lymphoma, 1.6% Marginal Zone B Lymphoma, 6.1% MALT, 1.6% Burkitt Lymphoma. T cell lymphomas were distributed in: Peripheral T Cell 253 (46.36%), Cutaneous Anaplastic 42 (16.09%), T/NKcell 35 (13.40%), Lymphoblastic 28 (6.16%), T non classifiable 10 (3.83%). The second group included 344 lymphomas; 309 (89.82%) B Cell NHL and 31 (10.01%) T cell Lymphomas. Gender 51.7 male and 48.3 female, medium age 57.79 years (SD 16.09); . >60 years 44%. After applying the FLIPI index the distribution of patients was 24.5% with intermedium risk and 9.5.8% high risk. Patients were divided into three IPI risk groups: Low 69.2% Intermediate 23% and high risk 7.8%. The frequencies of B cell lymphomas subtype were: DLBCL 168 (52.3%), Follicular 58(18.4%), CLL/SLL 19 (6.14%), Mantle Cell 10 (3.2%), Follicle Center Lymphoma (0.9%), Marginal Zone B 4 (1.2%), MALT 14 (4.5%), Burkitt’s Lymphoma 5 (1.6%). The T Cell Lymphoma subgroup frequencies were: T Cell Peripheral 7 (22.5%), Cutaneous Anaplastic 5 (16.1%), N/K cell 4 (12.9), Lymphoblastic 3 (9.6%), T lymphoma non classifiable 6 (19%). Conclusions: We confirmed a high incidence of T cell NHL in consecutive registries in Mexico. In the B cell subgroup it seems to be a difference where the DLBCL has a higher frequency and the CLL/SLL subgroup the lowest compared with other series. These differences in frequency might be explained by ethnic characteristics, however we need more epidemiological and viral studies, looking for Epstein Barr virus.

scholarly journals The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Christopher Rushton ◽  
Miguel Alcaide ◽  
Matthew Cheung ◽  
Neil R Michaud ◽  
Scott Daigle ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Treatment Resistance ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Liquid Biopsies ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are treated with standard frontline immunochemotherapy (R-CHOP). However, for cases where R-CHOP fails (relapsed-refractory DLBCL, rrDLBCL), prognosis is extremely poor, with 2-year overall survival of 20-40%. The successful development of new therapies may be hampered by our limited understanding of the genetic and molecular mechanisms underpinning treatment resistance. For example, recent data from our group has highlighted novel mutations that emerge following treatment with R-CHOP. The contribution of copy-number variations (CNVs) towards treatment resistance has not yet been thoroughly explored. A more complete characterization of these genetic alterations may lead to new prognostic biomarkers or treatment strategies. Methods We analyzed exome sequencing data from 59 rrDLBCL cases derived from either tissue biopsies or liquid biopsies collected after relapse, including both unpublished and previously published cases (Schmitz et al. (2018) NEJM 378:1396-1407 and Morin et al. (2016) Clin Can Res 22(9)). We separately performed low-pass whole-genome sequencing (lpWGS, 0.1-1x coverage) on 45 rrDLBCL liquid biopsies with ctDNA levels insufficient for exome-based analysis, for a total of 104 cases with copy-number information. We identified CNVs from exome and lpWGS data using Sequenza and ichorCNA, respectively. Next, we identified significant peaks of recurrent gains and losses using GISTIC2. Comparison of these peaks to CNVs in a previously published diagnostic DLBCL cohort (Schmitz et al. (2018) NEJM 378:1396-1407) enabled the identification of events that were significantly more prevalent in rrDLBCL. Results Overall, the landscape of CNVs in rrDLBCL is reminiscent of diagnostic DLBCL, with recurrent amplifications of chromosome 7 (43/104, 41.3%) and 18q (42/104, 40.4%) and recurrent deletions of 6q (25/104, 24.0%) and 17p13 (39/104, 37.5%). We identified nine regions enriched for recurrent amplifications or deletions among rrDLBCLs. These include deletions of 17p13.1 (20.4% in diagnostic biopsies vs 41.3% of rrDLBCLs, q=8.53x10-5) and recurrent amplifications of 8q24 (18.5% vs 42.3%, q=5.72x10-7) and 7p22 (27.2% vs 57.9%, q=6.29x10-8). Many of these peaks represent focal events that are exceedingly rare in diagnostic DLBCL and do not contain established lymphoma-associated genes, including amplifications affecting 700kb of 6p11.2 (2.03% vs 7.69%, q=0.0178) and 500kb of 19p13.3 (6.7% vs 31.7%, q=9.99x10-10). Notably, the 6p11.2 amplifications were associated with inferior progression-free survival following R-CHOP (p=0.02), with most tumors harboring this alteration relapsing within 12 months. We also identified a novel, recurrent deletion affecting a 20mb region of 5q (2.78% vs 10.6%, q=0.00604) which was significantly deleted in rrDLBCL. For tumors with additional samples collected prior to R-CHOP and following salvage therapy, deletions of 5q appeared to emerge following frontline therapy and persisted after subsequent treatments, suggesting they may contribute to treatment resistance. Discussion The 17p13.1 deletion enriched in rrDLBCL encompasses TP53, which is a common target of somatic point mutations in rrDLBCL and associated with inferior treatment outcomes. The amplification of 8q24 and 7p22 include MYC and GNA12/CARD11, respectively, although these large events encompass numerous additional genes which may be the target of such events. Curiously, the focal 6p11.2 amplification only overlaps a handful of genes including miR_598, which has been predicted to target CD27 and CD38 and whose expression is upregulated in B-cell cell lines (Lawrie et al. (2008) Leukemia 22:1440-2446). Further investigation and validation of these events and their corresponding targets will provide insight into the biology of rrDLBCL and may reveal novel therapeutic targets. Disclosures Michaud: Epizyme: Current Employment. Daigle:Epizyme: Current Employment. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy. Kuruvilla:Merck: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Honoraria; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Antengene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; TG Therapeutics: Honoraria. Crump:Servier: Consultancy; Roche: Consultancy; Kite/Gilead: Consultancy. Assouline:BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Bayer: Consultancy; Curis Inc: Consultancy. Johnson:AbbVie: Research Funding; Roche/Genentech, Merck: Honoraria; Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie: Consultancy. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Morin:Celgene: Consultancy.

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