- Email: [email protected]
Genomic Abnormalities of Waldenström Macroglobulinemia and Related Low-Grade B-Cell Lymphomas
IWWM 2012 Proceedings
Genomic Abnormalities of Waldenström Macroglobulinemia and Related Low-Grade B-Cell Lymphomas Esteban Braggio, Rafael Fonseca Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 2, 198-201 © 2013 Elsevier Inc. All rights reserved. Keywords: Array-based comparative genomic hybridization, Low-grade B-cell lymphomas, Nuclear factor kappa B signaling pathway, Waldenström macroglobulinemia
Abstract Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88) - interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-B) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.
WM cases.1-6 Massively parallel DNA sequencing has recently showed that mutations in the myeloid differentiation factor gene 88 (MYD88) is close to a unifying event in WM, with activating mutations in 90% of patients.7 At the transcription level, gene expression profiling identified interleukin 6 as the top upregulated hit in WM.8,9 Furthermore, results of comparative expression profiling suggest that WM clustered far more close to chronic lymphocytic leukemia (CLL) than to multiple myeloma (MM).8 Although genetic analysis has provided certain understandings of WM pathogenesis, there is not a complete clear distinction between WM and related entities across B-cell neoplasias characterized with similar clinical presentations. Thus, monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin (Ig) M type shares with WM the presentation of an elevated IgM secretion, but the evidence of bone marrow infiltration by lymphoplasmacytic lymphoma on a bone biopsy is characteristic of WM.10 Additional entities to consider in the differential diagnosis include marginal zone lymphoma (MZL), CLL, and MM. The aim of this study is to summarize the high throughput genomic analyses our group performed that compared large series of WM and related B-cell malignancies to better dissect the genetic similarities and differences between these entities.
Introduction Genomic and transcriptomic analyses have significantly improved our knowledge of the molecular basis of Waldenström macroglobulinemia (WM). Conventional cytogenetics and array-based comparative genomic hybridization have shown deletion of chromosome 6q in nearly half of patients with WM, followed by gains of chromosomes 3, 4, 18, 6p, and losses of 11q23 (ATM), 13q14 (MIRN15A/ 16-1), and 17p (TP53), each one being found in 10% to 20% of
Department of Hematology, Oncology, Mayo Clinic, Scottsdale, AZ Address for correspondence: Rafael Fonseca, MD, 13400 East Shea Boulevard, Mayo Clinic, Collaborative Research Building, Room 1–105, Scottsdale, AZ 85259-5494 E-mail contact: [email protected]
198
Clinical Lymphoma, Myeloma & Leukemia April 2013
Materials and Methods We analyzed 42 WM, 14 lymphoplasmacytic lymphomas (LPL) without monoclonal IgM protein (IgM), 20 MGUS, 35 splenic MZL, 20 nodal MZL, 46 mucosa associated lymphoid tissue (MALT) lymphoma, and 52 CLL cases. The WM cell population was enriched from bone marrow biopsy specimens by using antiCD19⫹ immunomagnetic beads or by a concomitant positive selection by using anti-CD19⫹ and CD138⫹. The MGUS cell population was enriched by using anti-CD138⫹ and CLL cells by using anti-CD19⫹ beads. Overall, ⬎90% purity was obtained in all samples after enrichment. In the non-IgM LPL, splenic MZL, nodal MZL, and MALT lymphomas, tumor purity was estimated by the percentage of CD20⫹ cells, including only cases with more than
2152-2650/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.02.015
MM
MC L
L MG US
LP
M W
lgM no
n-
SM ZL MM ZL MA LT
25 20 15 10 5 0
CL L
Median number of CNA
Figure 1 Comparison of the Median Number of Copy Number Abnormalities (CNA) (surrogate of genomic complexity) Between Waldenström Macroglobulinemias (WM) and Multiple B-cell Malignancies
70% tumor purity. In addition, data from 45 mantle cell lymphomas (MCL) and 240 MM (CD138⫹) were used as an outlier group for comparative purposes. Samples were analyzed with the Agilent 244K and Sureprint G3 microarray platforms (Agilent Technologies, Santa Clara, CA), which posses 243,000 and 1 million probes spread around the genome, respectively. This approach allowed the detection of copynumber abnormalities (CNA) found in at least 30% to 40% of tumor cells. Data were analyzed by using Genomic Workbench (Agilent) and Nexus (Biodiscovery) software. CNAs were only considered when at least 2 consecutive probes showed the abnormality. Finally, we eliminated copy-number polymorphisms from the analysis by using a combination of our own data and the Database of Genomics Variants (http://projects.tcag.ca/variation/).
Results and Discussion Overall, 35 patients (83%) with WM have an altered genome, as detected by array-based comparative genomic hybridization analysis, with a median of 4 CNAs per case (range, 0-27).1 By considering the genomic complexity, WM samples are in the same range of CLL samples (3 CNAs per sample; range, 0-32), SMZL samples (3 CNAs per sample; range, 0-66), NMZL samples (3.5 CNAs per sample; range, 0-35), and MALT lymphoma samples (4 CNAs per sample; range, 0-18) but considerably lower than MCL (15 CNAs per sample), MGUS (15 CNAs per sample), and MM (20 CNAs per sample) (Figure 1). Interestingly, the remaining LPL (non-IgM LPL) showed a significantly higher genomic complexity than the WM-LPL, with a median of 7 CNAs per sample (range, 0-44).11 Another indication of the low complexity of the WM genome was the low prevalence of biallelic deletions and high-level amplifications. Overall, in the entire cohort of 42 patients with WM, we only found 3 biallelic deletions, an amount that is usually observed in a single patient with MM. Most of the recurrent abnormalities observed in WM are shared with other B-cell malignancies. A summary of all abnormalities detected per entity, type (gains and losses), prevalence, and chromosome location is shown in Figure 2. Deletion of chromosome 6q was observed in 18 cases (42%), with 2 minimal deleted regions located
in 6q21 and 6q23, respectively. These regions include genes PRDM1 (6q21) and TNFAIP3 (6q23), which have been recognized as key players in the pathogenesis of MZL, diffuse large B-cell lymphomas (DLBCL), and Hodgkin lymphoma.11-17 The simultaneous presence of trisomies 3 and 18 was commonly found in WM and across MZL entities. The same is observed with deletions on chromosomes 7q32 and 11q23 (ATM), which are recurrently affected in SMZL and CLL, respectively1,11,12 Deletion on chromosome 13 affects the microRNAs MIRN15A and MIRN16-1 on cytoband 13q14, similar to CLL and SMZL,1,2,12,18 but different from MM and NMZL, where the entire chromosome 13 is usually lost. Deletion of 17p13, which includes TP53, has been found in nearly 4 patients (10%) with WM1,3 and is common to most of B-cell neoplasias. Inactivating mutations of TRAF3 (located on cytoband 14q32.32) have significant implications that lead to constitutive activation of nuclear factor kappa B (NF-B) pathways and are recurrent findings in 5% of patients with WM.1 Increased activation in the NF-B signaling pathway has been observed in several B-cell tumors, such as MM, DLBCL, MZL, and others.13,19,20 Interestingly, trisomy 4, which is identified in nearly 8 patients (19%) with WM, seems to be unique in WM, not shared by any other low-grade B-cell malignancies, including the non-IgM LPL cases.2,11 Moreover, trisomy 4 has occasionally been found to be the sole genetic abnormality within patients with WM.1,6 Highresolution genomic studies have not been able to identify a minimal gained region or a candidate gene on chromosome 4. Although the clinical implication of trisomy 4 is not well understood, analysis of data suggests that 4q may play a role in increased susceptibility to WM.21 In a genome-wide linkage analysis performed on 11 families identified as high risk for WM, high linkage was found on cytoband 4q33-q34, which suggests both linkage and common susceptibility between patients with IgM MGUS and patients with WM.21 The past few years have been of a marked evolution in our knowledge of the molecular basis of WM pathogenesis. The incorporation of highthroughput analyses to the study of WM has led to the discovery of a plethora of genetic abnormalities and molecular pathways associated with the disease.1,2,7-9,11 In this study we showed a comparative genomic analysis of WM and related lymphomas, including non-IgM LPL, MGUS, CLL, and MZL as well as more aggressive entities, for example, MM. The analysis identifies a very stable karyotype in WM, comparable with CLL and MZL, but showing lower complexity than non-IgM LPL, MGUS, MCL, and MM.19,22,23 The analysis across entities exposes a similar scenario at the genomic level, with the presence of a common group of CNAs shared by several or all of the entities, with few WM-specific abnormalities.
Conclusion The main challenge in the postgenomics era is to identify “Achilles heels” to be exploited for drug discovery and to rapidly translate these insights into novel therapeutic strategies for patients with WM. The discovery of the very high prevalence of MYD88 mutations,7 together with the presence of recurrent abnormalities in TNFAIP3 and TRAF3,1 confirms the central role of the MYD88-IRAK4 and NF-B signaling pathway in WM pathogenesis and provides promising avenues searching for novel therapies to this still incurable disease.
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The Genomic Landscape of Waldenström’s Macroglobulinemia Figure 2 An Overview of the Copy-Number Abnormalities Identified in Waldenström Macroglobulinemia (WM) Compared With non–immunoglobulin (Ig) M Lymphoplasmacytic Lymphoma (LPL), Marginal Zone Lymphoma (MZL), and Chronic Lymphocytic Leukemia (CLL). Recurrent Trisomy 4 Is Unique to WM and Not Found in non-IgM LPL. Chromosomes 1 to Y Are Represented From Left to Right. Light Gray Blocks Represent Chromosome Gains, Whereas Dark Gray Blocks Represent Chromosome Losses. The Amplitude in Each Abnormal Region Represents the Frequency (%) of Each CopyNumber Abnormality
WM
1
2
3
4
5
6
7
8
9
10
11
12
13
14 15 16 17 18 19 20 21 22 X
0.4 0.2 0.0
non-WM/LPL
–0.4
CLL
–0.4
0.4 0.2 0.0
0.4 0.2 0.0
NMZL
SMZL
MALT
–0.4 0.4 0.2 0.0 –0.4 0.4 0.2 0.0 –0.4 0.4 0.2 0.0 –0.4
Acknowledgments E. Braggio is a recipient of the Marriott Specialized Workforce Development Awards in Individualized Medicine, the Henry Predolin Foundation Career Development Award, and the George Haub Family Career Development Award Fund in Cancer Research.
Disclosure R. Fonseca is a consultant for Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, and Lilly (all less than $10,000); and receives research support from Cylene, Onyx, and Celgene. E. Braggio has no conflicts of interest.
References 1. Braggio E, Keats JJ, Leleu X, et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia. Cancer Res 2009; 69:3579-88. 2. Braggio E, Keats JJ, Leleu X, et al. High-resolution genomic analysis in Waldenström’s macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas. Clin Lymphoma Myeloma 2009; 9:39-42. 3. Nguyen-Khac F, Lejeune J, Chapiro E, et al. Cytogenetic abnormalities in a cohort of 171 patients with Waldenström macroglobulinemia before treatment: clinical and biological correlations. Blood (ASH annual meeting abstracts) 2010; 116:Abstract 801. 4. Schop RF, Jalal SM, Van Wier SA, et al. Deletions of 17p13.1 and 13q14 are uncommon in Waldenström macroglobulinemia clonal cells and mostly seen at the time of disease progression. Cancer Genet Cytogenet 2002; 132:55-60. 5. Schop RF, Kuehl WM, Van Wier SA, et al. Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100:2996-3001.
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Clinical Lymphoma, Myeloma & Leukemia April 2013
6. Terré C, Nguyen-Khac F, Barin C, et al. Trisomy 4, a new chromosomal abnormality in Waldenström’s macroglobulinemia: a study of 39 cases. Leukemia 2006; 20:1634-6. 7. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 2012; 367:826-33. 8. Chng WJ, Schop RF, Price-Troska T, et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006; 108:2755-63. 9. Gutiérrez NC, Ocio EM, de las Rivas J, et al. Gene expression profiling of B lymphocytes and plasma cells from Waldenström’s macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 2007; 21:541-9. 10. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 2003; 30:110-5. 11. Braggio E, Dogan A, Keats JJ, et al. Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities. Mod Pathol 2012; 25:651-60. 12. Ferreira BI, García JF, Suela J, et al. Comparative genome profiling across subtypes of low-grade B-cell lymphoma identifies type-specific and common aberrations that target genes with a role in B-cell neoplasia. Haematologica 2008; 93:670-9. 13. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009; 459:717-21. 14. Chanudet E, Ye H, Ferry J, et al. A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands. J Pathol 2009; 217:420-30. 15. Honma K, Tsuzuki S, Nakagawa M, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 2009; 114:2467-75. 16. Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981-9.
Esteban Braggio, Rafael Fonseca 17. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712-6. 18. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002; 99:15524-9. 19. Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12:131-44. 20. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12:115-30.
21. McMaster ML, Goldin LR, Bai Y, et al. Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families. Am J Hum Genet 2006; 79:695-701. 22. Largo C, Saéz B, Alvarez S, et al. Multiple myeloma primary cells show a highly rearranged unbalanced genome with amplifications and homozygous deletions irrespective of the presence of immunoglobulin-related chromosome translocations. Haematologica 2007; 92:795-802. 23. Hartmann EM, Campo E, Wright G, et al. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. Blood 2010; 116:953-61.
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Genomic Abnormalities of Waldenström Macroglobulinemia and Related Low-Grade B-Cell Lymphomas Esteban Braggio, Rafael Fonseca Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 2, 198-201 © 2013 Elsevier Inc. All rights reserved. Keywords: Array-based comparative genomic hybridization, Low-grade B-cell lymphomas, Nuclear factor kappa B signaling pathway, Waldenström macroglobulinemia
Abstract Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88) - interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-B) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.
WM cases.1-6 Massively parallel DNA sequencing has recently showed that mutations in the myeloid differentiation factor gene 88 (MYD88) is close to a unifying event in WM, with activating mutations in 90% of patients.7 At the transcription level, gene expression profiling identified interleukin 6 as the top upregulated hit in WM.8,9 Furthermore, results of comparative expression profiling suggest that WM clustered far more close to chronic lymphocytic leukemia (CLL) than to multiple myeloma (MM).8 Although genetic analysis has provided certain understandings of WM pathogenesis, there is not a complete clear distinction between WM and related entities across B-cell neoplasias characterized with similar clinical presentations. Thus, monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin (Ig) M type shares with WM the presentation of an elevated IgM secretion, but the evidence of bone marrow infiltration by lymphoplasmacytic lymphoma on a bone biopsy is characteristic of WM.10 Additional entities to consider in the differential diagnosis include marginal zone lymphoma (MZL), CLL, and MM. The aim of this study is to summarize the high throughput genomic analyses our group performed that compared large series of WM and related B-cell malignancies to better dissect the genetic similarities and differences between these entities.
Introduction Genomic and transcriptomic analyses have significantly improved our knowledge of the molecular basis of Waldenström macroglobulinemia (WM). Conventional cytogenetics and array-based comparative genomic hybridization have shown deletion of chromosome 6q in nearly half of patients with WM, followed by gains of chromosomes 3, 4, 18, 6p, and losses of 11q23 (ATM), 13q14 (MIRN15A/ 16-1), and 17p (TP53), each one being found in 10% to 20% of
Department of Hematology, Oncology, Mayo Clinic, Scottsdale, AZ Address for correspondence: Rafael Fonseca, MD, 13400 East Shea Boulevard, Mayo Clinic, Collaborative Research Building, Room 1–105, Scottsdale, AZ 85259-5494 E-mail contact: [email protected]
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Clinical Lymphoma, Myeloma & Leukemia April 2013
Materials and Methods We analyzed 42 WM, 14 lymphoplasmacytic lymphomas (LPL) without monoclonal IgM protein (IgM), 20 MGUS, 35 splenic MZL, 20 nodal MZL, 46 mucosa associated lymphoid tissue (MALT) lymphoma, and 52 CLL cases. The WM cell population was enriched from bone marrow biopsy specimens by using antiCD19⫹ immunomagnetic beads or by a concomitant positive selection by using anti-CD19⫹ and CD138⫹. The MGUS cell population was enriched by using anti-CD138⫹ and CLL cells by using anti-CD19⫹ beads. Overall, ⬎90% purity was obtained in all samples after enrichment. In the non-IgM LPL, splenic MZL, nodal MZL, and MALT lymphomas, tumor purity was estimated by the percentage of CD20⫹ cells, including only cases with more than
2152-2650/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.02.015
MM
MC L
L MG US
LP
M W
lgM no
n-
SM ZL MM ZL MA LT
25 20 15 10 5 0
CL L
Median number of CNA
Figure 1 Comparison of the Median Number of Copy Number Abnormalities (CNA) (surrogate of genomic complexity) Between Waldenström Macroglobulinemias (WM) and Multiple B-cell Malignancies
70% tumor purity. In addition, data from 45 mantle cell lymphomas (MCL) and 240 MM (CD138⫹) were used as an outlier group for comparative purposes. Samples were analyzed with the Agilent 244K and Sureprint G3 microarray platforms (Agilent Technologies, Santa Clara, CA), which posses 243,000 and 1 million probes spread around the genome, respectively. This approach allowed the detection of copynumber abnormalities (CNA) found in at least 30% to 40% of tumor cells. Data were analyzed by using Genomic Workbench (Agilent) and Nexus (Biodiscovery) software. CNAs were only considered when at least 2 consecutive probes showed the abnormality. Finally, we eliminated copy-number polymorphisms from the analysis by using a combination of our own data and the Database of Genomics Variants (http://projects.tcag.ca/variation/).
Results and Discussion Overall, 35 patients (83%) with WM have an altered genome, as detected by array-based comparative genomic hybridization analysis, with a median of 4 CNAs per case (range, 0-27).1 By considering the genomic complexity, WM samples are in the same range of CLL samples (3 CNAs per sample; range, 0-32), SMZL samples (3 CNAs per sample; range, 0-66), NMZL samples (3.5 CNAs per sample; range, 0-35), and MALT lymphoma samples (4 CNAs per sample; range, 0-18) but considerably lower than MCL (15 CNAs per sample), MGUS (15 CNAs per sample), and MM (20 CNAs per sample) (Figure 1). Interestingly, the remaining LPL (non-IgM LPL) showed a significantly higher genomic complexity than the WM-LPL, with a median of 7 CNAs per sample (range, 0-44).11 Another indication of the low complexity of the WM genome was the low prevalence of biallelic deletions and high-level amplifications. Overall, in the entire cohort of 42 patients with WM, we only found 3 biallelic deletions, an amount that is usually observed in a single patient with MM. Most of the recurrent abnormalities observed in WM are shared with other B-cell malignancies. A summary of all abnormalities detected per entity, type (gains and losses), prevalence, and chromosome location is shown in Figure 2. Deletion of chromosome 6q was observed in 18 cases (42%), with 2 minimal deleted regions located
in 6q21 and 6q23, respectively. These regions include genes PRDM1 (6q21) and TNFAIP3 (6q23), which have been recognized as key players in the pathogenesis of MZL, diffuse large B-cell lymphomas (DLBCL), and Hodgkin lymphoma.11-17 The simultaneous presence of trisomies 3 and 18 was commonly found in WM and across MZL entities. The same is observed with deletions on chromosomes 7q32 and 11q23 (ATM), which are recurrently affected in SMZL and CLL, respectively1,11,12 Deletion on chromosome 13 affects the microRNAs MIRN15A and MIRN16-1 on cytoband 13q14, similar to CLL and SMZL,1,2,12,18 but different from MM and NMZL, where the entire chromosome 13 is usually lost. Deletion of 17p13, which includes TP53, has been found in nearly 4 patients (10%) with WM1,3 and is common to most of B-cell neoplasias. Inactivating mutations of TRAF3 (located on cytoband 14q32.32) have significant implications that lead to constitutive activation of nuclear factor kappa B (NF-B) pathways and are recurrent findings in 5% of patients with WM.1 Increased activation in the NF-B signaling pathway has been observed in several B-cell tumors, such as MM, DLBCL, MZL, and others.13,19,20 Interestingly, trisomy 4, which is identified in nearly 8 patients (19%) with WM, seems to be unique in WM, not shared by any other low-grade B-cell malignancies, including the non-IgM LPL cases.2,11 Moreover, trisomy 4 has occasionally been found to be the sole genetic abnormality within patients with WM.1,6 Highresolution genomic studies have not been able to identify a minimal gained region or a candidate gene on chromosome 4. Although the clinical implication of trisomy 4 is not well understood, analysis of data suggests that 4q may play a role in increased susceptibility to WM.21 In a genome-wide linkage analysis performed on 11 families identified as high risk for WM, high linkage was found on cytoband 4q33-q34, which suggests both linkage and common susceptibility between patients with IgM MGUS and patients with WM.21 The past few years have been of a marked evolution in our knowledge of the molecular basis of WM pathogenesis. The incorporation of highthroughput analyses to the study of WM has led to the discovery of a plethora of genetic abnormalities and molecular pathways associated with the disease.1,2,7-9,11 In this study we showed a comparative genomic analysis of WM and related lymphomas, including non-IgM LPL, MGUS, CLL, and MZL as well as more aggressive entities, for example, MM. The analysis identifies a very stable karyotype in WM, comparable with CLL and MZL, but showing lower complexity than non-IgM LPL, MGUS, MCL, and MM.19,22,23 The analysis across entities exposes a similar scenario at the genomic level, with the presence of a common group of CNAs shared by several or all of the entities, with few WM-specific abnormalities.
Conclusion The main challenge in the postgenomics era is to identify “Achilles heels” to be exploited for drug discovery and to rapidly translate these insights into novel therapeutic strategies for patients with WM. The discovery of the very high prevalence of MYD88 mutations,7 together with the presence of recurrent abnormalities in TNFAIP3 and TRAF3,1 confirms the central role of the MYD88-IRAK4 and NF-B signaling pathway in WM pathogenesis and provides promising avenues searching for novel therapies to this still incurable disease.
Clinical Lymphoma, Myeloma & Leukemia April 2013
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The Genomic Landscape of Waldenström’s Macroglobulinemia Figure 2 An Overview of the Copy-Number Abnormalities Identified in Waldenström Macroglobulinemia (WM) Compared With non–immunoglobulin (Ig) M Lymphoplasmacytic Lymphoma (LPL), Marginal Zone Lymphoma (MZL), and Chronic Lymphocytic Leukemia (CLL). Recurrent Trisomy 4 Is Unique to WM and Not Found in non-IgM LPL. Chromosomes 1 to Y Are Represented From Left to Right. Light Gray Blocks Represent Chromosome Gains, Whereas Dark Gray Blocks Represent Chromosome Losses. The Amplitude in Each Abnormal Region Represents the Frequency (%) of Each CopyNumber Abnormality
WM
1
2
3
4
5
6
7
8
9
10
11
12
13
14 15 16 17 18 19 20 21 22 X
0.4 0.2 0.0
non-WM/LPL
–0.4
CLL
–0.4
0.4 0.2 0.0
0.4 0.2 0.0
NMZL
SMZL
MALT
–0.4 0.4 0.2 0.0 –0.4 0.4 0.2 0.0 –0.4 0.4 0.2 0.0 –0.4
Acknowledgments E. Braggio is a recipient of the Marriott Specialized Workforce Development Awards in Individualized Medicine, the Henry Predolin Foundation Career Development Award, and the George Haub Family Career Development Award Fund in Cancer Research.
Disclosure R. Fonseca is a consultant for Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, and Lilly (all less than $10,000); and receives research support from Cylene, Onyx, and Celgene. E. Braggio has no conflicts of interest.
References 1. Braggio E, Keats JJ, Leleu X, et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia. Cancer Res 2009; 69:3579-88. 2. Braggio E, Keats JJ, Leleu X, et al. High-resolution genomic analysis in Waldenström’s macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas. Clin Lymphoma Myeloma 2009; 9:39-42. 3. Nguyen-Khac F, Lejeune J, Chapiro E, et al. Cytogenetic abnormalities in a cohort of 171 patients with Waldenström macroglobulinemia before treatment: clinical and biological correlations. Blood (ASH annual meeting abstracts) 2010; 116:Abstract 801. 4. Schop RF, Jalal SM, Van Wier SA, et al. Deletions of 17p13.1 and 13q14 are uncommon in Waldenström macroglobulinemia clonal cells and mostly seen at the time of disease progression. Cancer Genet Cytogenet 2002; 132:55-60. 5. Schop RF, Kuehl WM, Van Wier SA, et al. Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100:2996-3001.
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