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  • 1
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    TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma
    Springer Science and Business Media LLC ; 2020
    In:  Nature Medicine Vol. 26, No. 4 ( 2020-04), p. 577-588
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 26, No. 4 ( 2020-04), p. 577-588
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/s41591-020-0757-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 2
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    Clinical Significance of Genetic Aberrations in Diffuse Large B Cell Lymphoma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 703-703
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 703-703
    Abstract: Background: Although R-CHOP has significantly improved outcome in diffuse large B-cell lymphoma (DLBCL), 40% of patients still experience relapsed/refractory disease. Further investigation into the genomic architecture of DLBCL is needed to determine the biological correlates that underlie treatment failure. Recent studies using next-generation sequencing strategies have described the landscape of recurrent mutations in DLBCL. However, with the exception of TP53 and FOXO1, little is known about the clinical relevance of recurrent mutations and importantly, the interactions of these genetic alterations in DLBCL. Moreover, an integrated analysis of copy number alterations and recurrent mutations annotated across cell-of-origin (COO) distinctions for a large cohort of DLBCL cases who have received uniform therapy is lacking. The present study examined the frequency and clinical impact of recurrent genetic aberrations of DLBCL using high-resolution technologies in a large population-based DLBCL cohort. Methods: We analyzed 348 newly diagnosed DLBCL cases that were uniformly treated with R-CHOP at the BC Cancer Agency (Vancouver) with available DNA extracted from fresh frozen biopsy material (tumor content 〉 30%). Matched germ line DNA was available for 67 patients. Comprehensive clinical annotation was available through the BCCA Lymphoid Cancer Database. Targeted re-sequencing of the coding exons of 56 genes was performed using a Truseq Custom Amplicon assay. Gene selection was based on mutational frequencies that have been previously described in DLBCL mutational landscape publications. High-resolution copy number analyses were performed using Affymetrix SNP 6.0 arrays. Tissue microarrays were constructed using duplicate 0.6mm cores from 332 cases, and breakapart FISH assays for MYC, BCL2 and BCL6 and IHC staining for MYC, BCL2 and cell of origin proteins were performed. COO classification was available in 331 cases, according to gene expression profiling by the Lymph2Cx assay using the NanoString platform (Scott, Blood 2014;123) in 299 patients as well as Hans algorithm (Hans, Blood 2004;103) in 32 cases with low tumor content. 194 cases were assigned to GCB subtype, 107 cases, ABC/non-GCB and 30 were unclassifiable. Results: In the mutation analysis, we identified 2,757 SNVs and 245 small indels. The mean depth of coverage was 634. Recurrent mutation frequencies varied between 0 and 58, with a mean of 8.25 per case. 98% of cases harbored at least one mutation and 95% of cases multiple mutations. 10 mutated genes were detected significantly more frequently in the GCB subtype including CREBBP, GNA13, EZH2, TNFRSF14, IRF8,STAT3, BCL2, SGK1, MEF2B and CD83, and 4 mutated genes, MYD88, CD79B, PRDM1 and PIM1, in the ABC subtype. In the copy number analysis, 45 significant amplification peaks and 57 deletion peaks were revealed by the GISTIC algorithm. As previously reported, 9p21.3, including CDKN2A,were more frequently detected in the ABC subtypes. With a median follow up of 6.5 years for living patients, the 5 y disease specific survival (DSS) and time to progression (TTP) of all patients were 72% and 64%, respectively. The clinical cohort was representative of registry data from BC based on a comparison of patient characteristics and survival outcomes with 1,194 control DLBCL R-CHOP patients. The ABC subtype was significantly associated with an inferior DSS and TTP (both p 〈 0.0001). In univariate analyses we identified several gene mutations and copy number aberrations significantly associated with survival in all patients. Of these genes, MYD88 and TP53 mutations were associated with significantly inferior TTP in the ABC subtype (p=0.04) and GCB subtype (p=0.002), respectively, while TMEM30A, CREBBP, PIM1 and BTG1 mutations were associated with prognosis in DLBCL. Our analyses confirm the poor prognosis conferred by TP53 mutations in DLBCL and, importantly, identified several novel genetic alterations associated with survival stratified by COO distinctions. Conclusions: Our approach using next generation sequencing and high resolution SNP array provides an accurate estimation of frequency and clinical significance of recurrent genetic alterations of DLBCL in a uniformly R-CHOP-treated large population-based cohort of patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.703.703
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 3
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    Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC
    American Society of Hematology ; 2020
    In:  Blood ( 2020-10-29)
    Details
    In: Blood, American Society of Hematology, ( 2020-10-29)
    Abstract: When the WHO defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" entity has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than co-occurring translocations - i.e. copy number variations (CNVs). While the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a shared underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma (DLBCL) morphology. While BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, while MYC IHC has been proposed as a screening tool for FISH testing, two mechanisms were observed that uncoupled MYC rearrangement from IHC positivity. 1) low MYC mRNA expression and 2) false-negative immunohistochemistry (IHC) staining mediated by a single nucleotide polymorphism resulting in an asparagine to serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020007193
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 4
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    Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin–specific clinical impact
    American Society of Hematology ; 2017
    In:  Blood Vol. 129, No. 20 ( 2017-05-18), p. 2760-2770
    Details
    In: Blood, American Society of Hematology, Vol. 129, No. 20 ( 2017-05-18), p. 2760-2770
    Abstract: MYC and BCL2 genetic alterations are associated with COO subtype-specific clinical effect in R-CHOP-treated DLBCL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2016-11-747022
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
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  • 5
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    High-resolution architecture and partner genes of MYC rearrangements in lymphoma with DLBCL morphology
    American Society of Hematology ; 2018
    In:  Blood Advances Vol. 2, No. 20 ( 2018-10-23), p. 2755-2765
    Details
    In: Blood Advances, American Society of Hematology, Vol. 2, No. 20 ( 2018-10-23), p. 2755-2765
    Abstract: Genomic rearrangements in the MYC locus occur in ∼12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring MYC rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of MYC, BCL2, BCL6, and the immunoglobulin (IG) loci in 112 tumors with DLBCL morphology harboring MYC rearrangement. We characterized the location of the MYC rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the MYC coding region and in intron 1 (the “genic cluster”). Genic cluster rearrangements were enriched for translocations involving IGH (80%), whereas nongenic rearrangements occurred mostly downstream of the MYC gene with a variety of partners, including IGL and IGK. Other recurrent partners included BCL6, ZCCHC7, and RFTN1, which has not previously been described as a MYC partner. We compared 2 commercially available FISH break-apart assays for the MYC locus and observed discordant results in 32% of cases examined, including some with MYC-IGL and MYC-IGK rearrangements. In cases of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH), so-called “double-hit” lymphomas, the majority of MYC rearrangements had non-IG partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, MYC-IG rearrangements showed a trend toward inferior time to progression and overall survival compared with MYC–non-IG rearrangements. Our data reveal clinically relevant architecture of MYC rearrangements in lymphomas with DLBCL morphology.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2018023572
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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    Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study
    Public Library of Science (PLoS) ; 2016
    In:  PLOS Medicine Vol. 13, No. 12 ( 2016-12-13), p. e1002197-
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    In: PLOS Medicine, Public Library of Science (PLoS), Vol. 13, No. 12 ( 2016-12-13), p. e1002197-
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    ISSN: 1549-1676
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    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2016
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  • 7
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    Abstract 2445: Integrative genetic analysis identifies therapeutic relevance of cell of origin-specific genetic alterations in diffuse large B-cell lymphoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2445-2445
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2445-2445
    Abstract: Introduction: Diffuse large B-cell lymphoma (DLBCL) comprises two distinct cell-of-origin (COO) subtypes: the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) subtypes. Several sequencing studies have informed on DLBCL biology and identified numerous candidate genes implicated in pathogenesis. However, comprehensive analysis of recurrent genetic alterations, and related prognostic significance according to COO subtypes has not yet been performed. To understand the molecular distinctions and their therapeutic relevance specific to COO subtype in DLBCL, we performed a comprehensive genetic analysis on a population registry-based cohort of 347 patients with de novo DLBCL uniformly treated with R-CHOP. Methods: Tissue biopsies from 347 patients were analyzed using deep amplicon sequencing of 58 genes, Affymetrix SNP 6.0 arrays, and RNAseq. Immunohistochemical staining was performed on tissue microarrays. COO subtype was assigned by Lymph2Cx assay. Results: We detected COO-specific mutations, copy number alterations (CNAs) and gene fusions. Furthermore, integrative analysis showed COO-specific trans gene expression effects on CNAs, demonstrating that CNAs in GCB-DLBCL are tightly linked to the deregulation of networks associated with PI3K-AKT signaling. We also identified the significant prognostic impact of recurrent genetic alterations within each COO subtype, including deletions of MIR15a/16-1 and TP53 and NFATC1 gain in ABC-DLBCL, TP53 and CREBBP mutations, PRAME deletions and MYC gain in GCB-DLBCL. In addition, deletions of PTEN and INPP4B, which are negative regulators of PI3K-AKT signaling, were individually associated with poor outcome in GCB-DLBCL (p=0.01 and p=0.045, respectively). Furthermore, patients whose tumors harbored both genetic alterations had an even worse prognosis (p=0.004), suggesting the clinical importance of PI3K-AKT signaling in GCB-DLBCL. Based on these genetic data, we found that the PI3K-AKT signaling pathway was more commonly altered in GCB-DLBCL than in ABC-DLBCL (64% vs 23%, p & lt;0.0001). We also confirmed frequent genetic alterations involved in the BCR-NFκB signaling pathway in ABC-DLBCL (80%), while this pathway was less frequently altered in GCB-DLBCL (54%; p & lt;0.0001). In addition, epigenetic modification and immune recognition pathways were more commonly altered in GCB-DLBCL compared to ABC-DLBCL (70% vs 44%; p & lt;0.0001, 71% vs 56%; p=0.015, respectively). Finally, we demonstrated that the majority of DLBCL cases are altered for at least two of the four pathways mentioned above (86% of ABC-DLBCL and 87% GCB-DLBCL). Conclusion: we describe the landscape of common genetic aberrations in a population-based uniformly-treated DLBCL cohort, broadly representative of patients treated with curative intent, providing the genetic foundation for implementing precision medicine in this disease. Citation Format: Daisuke Ennishi, Ali Bashashati, Saeed Saberi, Anja Mottok, Barbara Meissner, Merrill Boyle, Susana Ben-Neriah, Robert Kridel, Kerry J. Savage, Laurie H. Sehn, Joseph M. Connors, Ryan D. Morin, Marco A. Marra, Sohrab P. Shah, Christian Steidl, David W. Scott, Randy D. Gascoyne. Integrative genetic analysis identifies therapeutic relevance of cell of origin-specific genetic alterations in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2445. doi:10.1158/1538-7445.AM2017-2445
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    The Double-Hit Gene Expression Signature Defines a Clinically and Biologically Distinct Subgroup within GCB-DLBCL
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 921-921
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 921-921
    Abstract: Recognizing biological heterogeneity in diffuse large B-cell lymphoma (DLBCL), significant effort has been made to define distinct molecular subgroups of prognostic importance which harbor potentially targetable biology. Reflecting this, in the recent revision of the WHO classification, DLBCL was divided into cell-of-origin molecular subtypes and a new entity was defined - high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH). ~8% of tumors with DLBCL morphology are HGBL-DH/TH and all HGBL-DH/TH with BCL2 translocations (HGBL-DH/TH-BCL2) are of the GCB molecular subtype. To explore specific biology operating in HGBL-DH/TH-BCL2, we analyzed RNAseq data from 157 de novo GCB DLBCL tumors (25 being HGBL-DH/TH-BCL2) with the aim of defining gene expression signatures that distinguish such cases from other GCB-DLBCLs. We identified 104 genes that were most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB-DLBCLs, defined as having a 95% confidence interval of the Importance Score that did not cross 0. A model constructed from the expression of these genes clustered 42 tumors into one group ("double-hit signature" positive - DHITsig pos), and 115 tumors into the DHITsig neg group. 22 tumors were HGBL-DH/TH-BCL2 within the DHITsig pos group compared with only 3 tumors in the DHITsig neg group. We next assessed the clinical impact of the DHITsig within a uniformly R-CHOP treated cohort of de novo GCB-DLBCL drawn from a population-based registry, which included the discovery cases. The DHITsig pos group had significantly inferior outcomes for time to progression (TTP) and overall survival (OS) (P & lt; 0.001 and P = 0.01, respectively) similar to ABC-DLBCL (Figs A, B). Notably, the non-HGBL-DH/TH-BCL2 cases sharing the DHITsig showed the same poor prognosis as the HGBL-DH/TH-BCL2 cases. A multivariate Cox model of TTP revealed that DHITsig remained prognostic, independent of IPI and MYC/BCL2 dual protein expression (HR = 3.1 [1.5 - 6.4], P = 0.002). We then applied this gene expression model to GCB-DLBCL in an independent dataset (n = 262 GCB-DLBCLs; Reddy et al,Cell 2017). Validating the prognostic significance, the DHITsig pos group had significantly inferior OS compared with other GCB-DLBCLs (P & lt; 0.001) similar to ABC-DLBCL (Fig C). We then sought to determine whether differentially expressed genes, according to DHITsig, could inform on the biology of the DHITsig pos group. Gene set enrichment analysis (GSEA) strongly suggested a germinal centre dark-zone (DZ) cell-of-origin for the DHITsig pos tumors with significant enrichment of DZ and light-zone (LZ) gene signatures (Victora et al, Blood 2012) in DHITsig pos and neg tumors, respectively (FDR = 0.002 and & lt; 0.001). Furthermore, the DHITsig pos group had up-regulation of pathways related to mitochondrial metabolism and RNA synthesis (both FDR & lt; 0.001). We separately identified mutations associated with DHITsig pos cases within GCB-DLBCL. In addition to the expected enrichment of MYC and BCL2 mutations, chromatin modifiers EZH2 and CREBBP, as well as RFX7 and DDX3X (mutated in Burkitt lymphoma), were more frequently mutated in DHITsig pos tumors. In contrast, mutations of TNFAIP3, MYD88 and IRF4, more typical of ABC-DLBCLs, were more prevalent in DHITsig neg tumors. To enable application to FFPE biopsies, the DLBCL90 NanoString assay was developed by translating the DHIT gene expression signature into a 30-gene module that was then added to the Lymph2Cx assay. The DLBCL90 assay was applied to 171 DLBCL tumors (including 156 from the discovery cohort), yielding 26% DHITsig pos, 64% DHITsig neg, and 10% unclassified, with a frank misclassification rate of 3% against the RNAseq comparator. The prognostic significance of the groups was maintained (Fig D). Importantly, the DHITsig neg group had a disease specific survival of 91% at 5 years. To validate the association between the DHITsig and HGBL-DH/TH-BCL2 tumors, the DLBCL90 assay was applied to 113 transformed follicular lymphoma tumors. Within the DHITsig pos group, 19/34 tumors were HGBL-DH/TH-BCL2 compared with 0/58 in the DHITsig neg group. In conclusion, we have identified a clinically and biologically distinct subgroup of GCB-DLBCL tumors that are defined by the HGBL-DH/TH-BCL2 gene signature. The translation to an assay applicable to FFPE allows exploration of its utility to guide patient management within the context of clinical trials. Figure. Figure. Disclosures Sehn: Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Steidl:Nanostring: Patents & Royalties: patent holding; Roche: Consultancy; Tioma: Research Funding; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy. Connors:Cephalon: Research Funding; Amgen: Research Funding; F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding; Bristol Myers-Squibb: Research Funding; Janssen: Research Funding; Bayer Healthcare: Research Funding; Takeda: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Merck: Research Funding; Genentech: Research Funding; Lilly: Research Funding. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Roche: Research Funding; Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116827
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 9
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    TP53 Expression Correlates with TP53 Mutations and Is an Independent Predictor of Clinical Outcome in Patients with DLBCL Treated with R-CHOP
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3964-3964
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3964-3964
    Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous neoplasm with 40% of patients experiencing treatment failure following immuno-chemotherapy (R-CHOP). Both cell-of-origin (COO) and presence of concurrent MYC/BCL2 rearrangements (DHIT) are significantly associated with distinct inferior outcome. Recently, next-generation sequencing (NGS) studies have uncovered distinct genetic subtypes, including a sizable ABC/GCB-independent group characterized by more frequent TP53 abnormalities. The patterns of TP53 mutations and the prognostic significance in DLBCL have been previously reported. However, such information is rarely available at the time of diagnosis as diagnosis of DLBCL for most patients is based on morphology and phenotype, assessed by immunohistochemistry (IHC). To bridge the gap between genotype and phenotype, we examined the TP53 mutational status and TP53 protein over-expression (IHC) in a large population-based DLBCL cohort uniformly treated with R-CHOP (Ennishi et al. Blood 2017 129:2760-2770). Methods: We analyzed 347 newly diagnosed de novo DLBCL cases uniformly treated with R-CHOP in British Columbia. Comprehensive clinical annotation was available through the BC Cancer Lymphoid Cancer Database. Deep targeted re-sequencing of the coding exons of TP53 was performed using a Truseq Custom Amplicon assay (Illumina) on the Miseq platform. IHC staining for TP53 (DO7), TP21, COO (Hans) and break-apart FISH assays for MYC and BCL2 were performed on tissue microarrays (n=332). COO classification was also performed using the Lymph2Cx assay (NanoString) (n=324). Strong TP53 expression (TP53+) was defined as high intensity (3/3) expression in 〉 50% of the malignant cells. Results: TP53 mutations (p53mut) were present in 72 cases (22.2%) with 84% being missense and 64% localized to the DNA binding-motifs. There were 54 TP53+ tumors by IHC (17%), of which 51 (94%) had p53mut, with a sensitivity of 70% for detection of p53mut. All but one TP53+ with p53mut (50/51 cases) had missense mutations. All TP53+ with missense p53mut (85% of all missense p53mut) showed strong nuclear expression, one recurrent nonsense p53mut showed combined cytoplasm/nuclear TP53+, while all splice site and frameshift variants were TP53+-negative. All TP53+ cases were negative for TP21; 30 (56%) cases were GCB (Hans) while 24 (44%) cases were non-GCB (Hans) and only 4 (16%) cases were DHIT. Both p53mut and TP53+ were associated with poor overall survival (OS) (p=0.004 and p=0.007, respectively) and disease-specific survival (DSS) (p=0.003 and p=0.001, respectively). In multivariate analysis with IPI, COO (Hans) and DHIT status, both p53mut and TP53+ were independent predictors of OS (HR=0.6, 95%CI=0.4-0.9, p=0.008 and HR=0.6, 95%CI=0.4-0.9, p=0.011, respectively) and DSS (HR=0.6, 95%CI=0.4-0.9, p=0.01 and HR=0.5, 95%CI=0.3-0.8, p=0.004, respectively). These results were consistent when the Lymph2Cx was used to assign COO (n = 324). Importantly, patients with TP53+ tumors showed significantly poorer outcome (OS and DSS) when compared with patients with tumors negative for TP53 stratified by both Hans COO subtypes (p=0.001 and p 〈 0.001, respectively) and DHIT tumors (p=0.02 and p=0.003, respectively). Conclusion: TP53+ shows good correlation with the presence and type of TP53 mutations and can be readily performed in routine clinical practice. TP53+ is a strong predictor of clinical outcome in DLBCL patients treated with R-CHOP and independent of IPI, COO and DHIT. TP53+ can be easily performed in current diagnostic laboratories and complements known biomarkers to better stratify DLBCL patients and potentially improve their clinical management. Figure Disclosures Villa: Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Sehn:Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Merck: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Steidl:Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-121943
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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    detail.hit.zdb_id: 80069-7
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  • 10
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    Targeted Sequencing Reveals Novel Gene Mutations Associated with Transformation and Early Progression in Follicular Lymphoma
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2919-2919
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2919-2919
    Abstract: Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency 〉 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2919.2919
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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