Genetic Abnormalities Involved in the Development and Progression of Follicular Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2049-2049
Author(s):  
Karen E Deffenbacher ◽  
George Wright ◽  
Javeed Iqbal ◽  
Huimin Geng ◽  
Derville O’Shea ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Follicular Lymphoma ◽  
Copy Number ◽  
Clinical Course ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Oncogenic Pathways ◽  
Insight Into

Abstract Background: Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and remains incurable by current therapeutic approaches. Clinical course is variable, and transformation into an aggressive lymphoma (t-FL) with marked worsening of prognosis occurs in 20–60% of patients. While Bcl2 gene translocation is a critical initiating event in the majority of FL cases, evidence indicates it is not sufficient for the development of a FL. Characterization of the genetic alterations subsequent to Bcl2 translocation will lend insight into the oncogenic pathways that contribute to FL pathogenesis and the molecular mechanisms underlying variability in clinical course. Methods: To define recurrent genomic copy number alterations (CNA) in FL, we performed high resolution array comparative genomic hybridization (aCGH) using the Affymetrix 500K SNP array platform. aCGH data were generated on a series of 112 FL cases with available gene expression profiling (GEP) and clinical information. Gene expression data were correlated with copy number data using the Gene Expression and Dosage Integrator (GEDI) algorithm developed at the NCI. Results: Selecting for abnormalities occurring in >10% of cases, the minimal common region (MCR) for 38 losses and 31 gains were defined. Novel common regions included gains on 15q11, 16p11, 5p14 and 19q13, and losses on 3q29, and 16p13. The MCR identified by aCGH were also compared with our existing cytogenetic data on 360 FL cases. MCR residing within the most frequent cytogenetic imbalances (>5%) were selected for analysis at the gene level to further refine these regions. These include gains on 1q21, 2p16, 7q11, 8q24, 12q13, 17q21, 18q21, 21q11, and X, and losses on 1p36, 6q, 10q, 13q34, and 17p13. Recurrent amplifications were detected for the 2p16, 15q11, and 17q21 MCR, while frequent uniparental disomy (UPD) was found to overlap the region of loss on 1p36. Recurrent UPD was also noted on 6p, 12q, 15q and 16p. For the majority of selected MCR, global expression of the genes residing in the MCR demonstrated an association with copy number status. Within these abnormalities, individual genes showing significant correlation with copy number were also identified. Conclusion: The combination of high resolution aCGH and GEP facilitated the identification of functionally relevant genes within the chromosomal abnormalities in FL. Delineation of these molecular targets will provide insight into the oncogenic pathways that contribute to FL disease pathogenesis and may provide novel therapeutic targets.

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.

Chromosomal Alterations in Gene Expression-Defined Pediatric Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2922-2922
Author(s):  
Karen E Deffenbacher ◽  
Javeed Iqbal ◽  
Zhongfeng Liu ◽  
Sherrie L. Perkins ◽  
Megan S Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chromosomal Alterations ◽  
Gene Signatures ◽  
Acgh Analysis ◽  
Pathogenetic Mechanisms

Abstract Abstract 2922 Poster Board II-898 Introduction: Lymphomas derived from mature lymphocytes in children and adolescents are predominantly aggressive B-cell non-Hodgkin lymphomas (B-NHL), including Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Differences in the clinical course between pediatric and adult aggressive B-NHL suggest distinct pathogenetic mechanisms. This study sought to identify both shared and unique genetic alterations between gene expression-defined pediatric and adult cases of BL and DLBCL. Patients and Methods: Gene expression profiling (GEP) was done on 45 BL and 18 DLBCL specimens from patients 18 years of age or younger, and 38 BL and 106 DLBCL from adult patients. Pediatric specimens were collected from the Cooperative Human Tissue Network (CHTN) pediatric NHL repository through the Children's Oncology Group (COG) and adult specimens were collected from the Nebraska Lymphoma Study Group Registry and Tissue Bank through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). Previously-published gene signatures were used to classify lymphomas molecularly into mBL and mDLBCL groups (Dave et al., NEJM, 2006). The mDLBCL tumors were further classified into activated B-cell-like (ABC), germinal center B-cell-like (GCB), and primary mediastinal B-cell lymphoma (PMBL) subtypes (Rosenwald et al., JEM, 2003). High resolution array comparative genomic hybridization (aCGH) was done on a subset of the pediatric cases using the 250K NspI Human Mapping Array (Affymetrix) to detect DNA copy number alterations (CNA). Results: Molecular classification of the pediatric cases resulted in a 20% reclassification rate for cases with a morphologic diagnosis of BL or DLBCL. Among the 63 pediatric cases, there were 38 mBL (3 of which were DLBCL by morphology), 23 mDLBCL (9 of which were BL by morphology) and two cases which were unclassifiable by the molecular gene signatures. Comparison of the GEP profiles for adult and pediatric mBL failed to identify pathways that differed significantly; however high resolution aCGH analysis revealed a number of abnormalities in the pediatric cases not previously reported in BL, including gains of 3q21, 11q13 and 16p11. A predominance of the GCB to ABC subtype (3:1) was found among pediatric mDLBCL patients. Two cases with mediastinal tumors were classified as PMBL molecularly. Both PMBL cases were female and carried copy number gains of the Rel/BCL11A locus. Comparison of adult and pediatric GCB mDLBCL gene expression revealed enrichment in B-cell surface molecules and markers of antigen-dependent B-cell activation in the adult cases. aCGH analysis identified abnormalities that were both shared (+12q15, +19q13, -6q) between adult and pediatric mDLBCL and unique (-4p14, -19q13.32, +16p11.2) to the pediatric cases. Correlation of DNA copy number and gene expression revealed potential candidate genes for these loci. Conclusions: Pediatric BL and DLBCL classified by morphology were reclassified molecularly in a significant fraction of cases. Although pediatric BL and DLBCL are treated similarly, defining homogeneous molecular entities will be relevant for developing new therapies and future clinical trials. In general, pediatric cases have a more favorable outcome relative to adult patients. However, it is unclear whether this is due to the ability of children to tolerate very intensive therapies or whether distinct pathogenetic mechanisms modulate the disease course. Higher B-cell receptor signaling in adult relative to pediatric GCB DLBCL may be relevant to the outcome. The identification of previously undetected chromosomal alterations unique to the pediatric cases also suggests distinct pathogenetic mechanisms. Elucidation of the underlying genes may provide insight into factors which modulate outcome and could provide novel therapeutic targets with reduced toxicity. Disclosures: Gascoyne: Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Simultaneous Detection of BCL2 Translocation and Copy Number Alteration Including Intrachromosomal Amplification in FL and DLBCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3955-3955
Author(s):  
Harinder Chhabra ◽  
Valentina Mizhiritskay ◽  
Charles Barnabe ◽  
Lya Josephine Montella ◽  
Viera Nelson ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Follicular Lymphoma ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Simultaneous Detection ◽  
B Cell Lymphoma ◽  
Chromosome Translocation ◽  
Comparative Genomic ◽  
Prognostic Information ◽  
Bcl2 Gene

Abstract Abstract 3955 Poster Board III-891 Causal overexpression of BCL2 protein in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) can be deregulated either by chromosome translocation t(14;18)(q32;q21) or by copy number increase (CNI) of the BCL2 gene, the latter of which includes gains of 18q and extra- or intra-chromosomal amplification. To study the utilization and advantages of interphase fluorescence in situ hybridization (FISH) testing, we retrospectively analyzed abnormal results from 226 consecutive cases with FL or DLBCL using a dual-color dual-fusion t(14;18)/IGH-BCL2 probe (Abbott, IL) performed on various types of specimens such as paraffin embedded tissue, lymph nodes and bone marrow aspirates. The t(14;18) was found in 133 cases (58.8%) with 5 of them also having one extra BCL2 signal, whereas the remaining 93 (41.2%) cases had increased copy number of BCL2 with a range of 3 to 60. In the CNI group, there were two patterns observed: scattered signals seen in the vast majority of cases; and large clusters of intrachromosomally amplified signals observed in two cases. In a concurrent metaphase cytogenetic analysis on the same tonsil sample in one patient with DLBCL, the amplified BCL2-containing segments were present as homogeneously staining region (hsr) on chromosome 13q as well as 18q with no double minutes or marker chromosomes detected. The second highly amplified case was incidentally found to have enlarged lymph nodes during vascular surgery and diagnosed as follicular lymphoma grade 1/3. Interestingly, FISH on paraffin embedded lymph nodes showed one large cluster of amplified BCL2 with an IGH signal within each cluster, suggesting a coexisting translocation t(14;18) and an amplification of BCL2 per se. The FISH patterns in these two highly amplified cases seem to represent a tandem duplication of the BCL2 gene. Although t(14;18) and BCL2 amplification are generally considered to be mutually exclusive in lymphomagenesis, our latter case may be the first reported one where t(14;18) and BCL2 amplification occurred concomitantly. Our study demonstrated that FISH testing with its high specificity, sensitivity and easy visibility for individual cells from various tissue types can simultaneously detect translocations and copy number alterations, provide valuable diagnostic/prognostic information in lymphoma stratification, and complement conventional cytogenetics and comparative genomic hybridization. Disclosures: No relevant conflicts of interest to declare.

Multiple Secondary Genetic Events Inducing Histologic Progression (HP) of Non-MALT Marginal Zone Lymphoma (MZL): An Integrated Genomic Analysis of Genome-Wide Copy-Number-Changes (CNC) and Transcriptomic Data.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1198-1198
Author(s):  
Lise Willems ◽  
Josette Briere ◽  
Mahatsangy Raharijaona ◽  
Benoit Ballester ◽  
Samuel Quentin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Array Cgh ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Comparative Genomic ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
Cyclin G

Abstract HP of indolent B cell lymphoma to a high grade lymphoma is usually associated with a rapidly progressive clinical course and a short survival. The risk of HP in MZL is evaluated around 10–20%, and can be detected at diagnosis or during the evolution of the disease. No criteria have been yet formally adopted to range HP, even in the more recent OMS classification, although therapeutic impact is important. In this study we wished to determine the genetic alterations implicated in the HP of non-MALT MZL, using an integrated analysis of genome-wide CNC and transcriptomic data. Fresh-frozen tumor biopsies and clinical data were obtained from 66 untreated non-MALT MZL patients of 3 institutions (SLS, HD, CHLS, France). Features reviews including morphologic aspect, immunophenotype, and conventional cytogenetics, classified 52 cases as MZL and 14 cases as MZL with HP (HP-MZL). HP was assessed by the presence of large cells, the presence of cohesive sheets of larges cells, and elevated Ki67. CNC were analysed in 20 splenic MZL (SMZL), in 6 HP-SMZL cases including 2 matched cases, and in 3 germ-line DNA of these cases using array comparative genomic hybridization (array-CGH) (Agilent, 105K). Normalization of the array-CGH data was realized by Lowess correction. Transcriptomic analysis of 32 SMZL and 8 HP-MZL, including 2 matched cases, was performed with a nylon DNA microarray of 9,216 human genes. After Lowess correction, data were visualized by hierarchical clustering allowing to distinguish patterns of gene expression corresponding to precise functions, cell or tissue subtype. The ability of individual transcripts to distinguish MZL and HP-MZL subtypes was calculated using discriminating score and bootstrap resampling. The most common imbalances detected by cytogenetics were gains of 3/3q (n=11/61, 18 %) and 18q (n=13/61, 21%), and deletions in 7q (n=18/61, 17%), and were detected in both groups, SMZL and HP-SMZL. Array-CGH analysis showed that no recurrent CNC was specific of all HP-SMZL. Only 1 CNC was present in 4 of the 6 HP-SMZL cases, 3 in 3 cases, and 29 in 2 cases. These CNC could also be seen in SMZL. Comparing the matched pairs, we identified secondary CNC changes. One was located in 4p and includes 9 genes. Among them, was Cyclin G associated kinase. This CNC was also present in 2 other HP-MZL cases. Another was located in 6p and includes 4 genes, comprising IRF4. Another HP-SMZL case exhibited a HP-SMZL specific CN gain of the oncogene Myc in 8q. These 3 genes are known to be involved in proliferation. Gene expression profiling showed overexpression of genes involved in proliferation and underexpression of p53 in HP-MZL cases compared to SMZL cases. The proliferation signature included PCNA, genes involved in glycolysis (GAPD, LDHA), in cell cycle (CDC10, CDK4), and cell proliferation (TNFRSF13B, MCL1). Two other signatures included genes overexpressed specifically in HP-MZL: one specific to the stroma with MIG, STAT1, Cathepsin B and C, CREG, IGFR2R; and a cluster of unknown function regrouping several oncogenes (DEK, DJ-1), genes related to cell machinery and cell motility (HMMR, PRPF4, PPOX) and genes involved in signal transduction (ZNF146, FLJ10618, PBXL2). In addition to p53, HP-MZL underexpressed genes included PMSB1 in the proteasome, KLF2 and PFC. In conclusion, integrated genetic and transcriptomic analyses of non-MALT MZL and HP-MZL showed that histologic progression was related to the alteration of cell proliferation. Beside chromosomal alterations typical to SMZL, secondary CNC could be detected in HP-SMZL cases. These CNC included genes associated with cell proliferation: Cyclin G associated Kinase, IRF4, and Myc. These results highlight that deregulation of different pathways drive the MZL cells toward a higher proliferative rate charateristic of histologic progression.

High-Resolution Comparative Genomic Hybridization of Mirna Genes In Therapy-Related AML Identifies a Somatic Deletion of MiR-223

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2759-2759
Author(s):  
Giridharan Ramsingh ◽  
Angela Matson ◽  
Matthew J. Walter ◽  
Daniel C. Link
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Copy Number ◽  
Genomic Dna ◽  
Mirna Gene ◽  
Gene Mutations ◽  
Epigenetic Silencing ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Mirna Genes

Abstract Abstract 2759 MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and diverse cellular processes. Expression profiling of miRNAs has identified dysregulated miRNAs in many cancers, including acute myeloid leukemia (AML). However, the mechanism for altered miRNA gene expression and the frequency of miRNA gene mutations in AML is largely unknown. We performed next-generation sequencing and high-resolution comparative genomic hybridization (CGH) to determine the frequency of miRNA gene mutations in 30 patients with therapy-related AML (t-AML). The sequencing is completed, and final analysis is underway. Herein, we report the results of the CGH. We designed custom CGH arrays for all 835 miRNA genes in miRBase (version 14) and 44 genes involved in miRNA processing. Average probe spacing was 30 bp for miRNA genes and 80 bp for miRNA processing genes and 10 kb flanking regions were interrogated for all genes. In each case, genomic DNA from leukemic blasts was compared with DNA from a skin biopsy from that patient. The median age of the 30 patients with t-AML was 49.2 years (25-77) with M:F ratio 13:17. The mean blast % was 81% (31-100). Consistent with previous reports, many of these patients had an abnormal karyotype with abnormalities of chromosome 5 and 7, 13% and 17% respectively. As expected, CGH analysis confirmed copy number alterations already identified by cytogenetics. In addition, we identified a single t-AML sample (from a male patient) that carried a small (435 kb) hemizygous deletion of miR-223 on chromosome × that was not apparent by cytogenetics. Quantitative PCR of genomic DNA confirmed the loss of the miR-223 gene, and real time RT-PCR demonstrated loss of miR-223 expression. Of note, miR-223 has been implicated in the regulation of granulopoiesis, and mice lacking miR-223 display a myeloproliferative phenotype (Johnnidis, Nature 2008). We screened an additional 27 AML patients for miR-223 expression and identified 3 other samples with miR-223 expression 2 standard deviations below the normal (based on CD34+ cells from healthy donors). No copy number alterations in miR-223 were detected in these patients, suggesting epigenetic silencing of miR-223. Consistent with this possibility, one of these patients carried a t(8;21), which has been shown to epigenetically silence miR-223 (Fazi, Cancer Cell 2007). The mechanism by which miR-223 is silenced in the other two AML samples is under investigation. In summary, cytogenetically silent deletions of miRNA genes are uncommon in t-AML. Loss of miR-223 expression can occur through somatic mutation or epigenetic silencing and is likely to contribute to leukemic transformation in a subset of patients with AML. Disclosures: No relevant conflicts of interest to declare.

Clinical Significance of Genetic Aberrations in Diffuse Large B Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 703-703 ◽  
Author(s):  
Daisuke Ennishi ◽  
Christoffer Hoffer ◽  
Hennady Shulha ◽  
Anja Mottok ◽  
Pedro Farinha ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Large Population ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Genetic Alterations ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Recurrent Mutations ◽  
Generation Sequencing

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.

scholarly journals A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 665 ◽  
Author(s):  
Marguerite Tyran ◽  
Nadine Carbuccia ◽  
Séverine Garnier ◽  
Arnaud Guille ◽  
José Adelaïde ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Copy Number ◽  
Genomic Analysis ◽  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Tyrosine Kinase Receptor ◽  
Cdk Inhibitors ◽  
Breast Cancers

Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC–BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.

scholarly journals DNA copy number changes in diffuse large B-cell lymphoma--comparative genomic hybridization study

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5269-5278 ◽  
Author(s):  
O Monni ◽  
H Joensuu ◽  
K Franssila ◽  
S Knuutila
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
B Cell Lymphoma ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Primary Tumors ◽  
Large B Cell Lymphoma ◽  
Recurrent Tumors ◽  
Copy Number Changes ◽  
High Level

We studied DNA copy number changes in diffuse large B-cell lymphoma using comparative genomic hybridization analysis on 20 primary tumors and on 12 recurrent tumors excised after chemotherapy or radiotherapy. Twenty-nine (91%) of the cases showed abnormal copy number karyotypes. Chromosomal regions at X (41%), 1q (38%), 7 (31%), 3 (24%), 6p (21%), 11 (21%), 12 (21%), and 18 (21%) were most frequently gained, and the most common losses involved 6q (38%), X (21%), 1p (14%), and 8p (10%). High-level amplifications were observed at 6p23-ter, 10p12–14, 17p1l.2, 18q21-ter, and Xq22-ter, all but 18q appearing only in the recurrent tumors. Gains (median, 2; range, 0 to 10) were more frequent than losses (median, 1; range, 0 to 7; P = .0004). The median number of aberrations found in the recurrent tumors (6.5) was greater than that in the primary tumors (2; P = .01). The copy number changes found in the recurrent tumors were more random than those found in the primary tumors, which were mainly located in the most frequently affected regions. Our findings are in line with those observed using conventional cytogenetic analysis, but especially novel high-level amplifications were detected. Southern blot analysis showed BCL2 amplification, but not translocation t(14;18)(q32;q21), in cases in which a gain at 18q was detected by comparative genomic hybridization, which strongly suggests that, in addition to translocation, gene amplification is another mechanism for the overexpression of the BCL2 protein.

Sign in / Sign up

Export Citation Format

Share Document