REVIEW ARTICLE
Genetics of Diffuse Large B-Cell Lymphoma Paving a Path to Personalized Medicine Rebecca L. King, MD,* and Adam Bagg, MDÞ
Abstract: Diffuse large B-cell lymphoma, the most common type of lymphoma in Western countries, remains incurable in approximately 40% of patients. Over the past decade, nascent molecular technologies have led to the discovery of many of the genetic events underlying the pathogenesis of this group of diseases. Whether by defining gene signatures that subclassify diffuse large B-cell lymphoma into subgroups, dysregulation of key cellular pathways, or specific mutations, we are approaching an era in which personalized diagnostics, prognostication, and therapy are imminent. Key Words: Diffuse large B-cell lymphoma, personalized diagnostics, nascent molecular technologies (Cancer J 2014;20: 43Y47)
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lthough the most recent publication of the World Health Organization classification acknowledges several distinct variants and subtypes of diffuse large B-cell lymphoma (DLBCL), primarily based on morphologic and clinical features, the vast majority of cases fall under the DLBCL, not otherwise specified (DLBCL NOS) category. Although this classification scheme simplifies the diagnosis of such lymphomas for the pathologist, it unsurprisingly results in a heterogeneous group of tumors with much clinical variation. The earliest attempts to subclassify DLBCL NOS (referred to as DLBCL in this review) were focused on the cytopathologic features of either centroblastic or immunoblastic large B cells.1 In addition to cytopathology, the anatomic site of presentation may, in some cases, predict clinical behavior and thus has become the basis for many of the subclasses of DLBCL. Although the addition over a decade ago of the anti-CD20 monoclonal antibody, rituximab, to multiagent chemotherapy markedly improved outcomes in DLBCL, 30% to 40% of patients continue to demonstrate suboptimal responses to therapy.2 This underscores the need for better prognostic and predictive markers, as well as potential therapeutic targets, and has fueled prolific investigation into the genetic basis of DLBCL. This review summarizes the wealth of literature on the molecular pathogenesis of DLBCL focusing on attempts to define clinically relevant subsets of disease and novel therapeutic targets.
GENE EXPRESSION PROFILING In the early 2000s, gene expression profiling (GEP) using microarrays provided much insight into the biologic heterogeneity of DLBCL. Early studies identified distinct signatures From the *Perelman School of Medicine at the University of Pennsylvania, The Children’s Hospital of Philadelphia; and †Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA. Reprints: Adam Bagg, MD, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 7.103 Founders Pavilion, 3400 Spruce St, Philadelphia, PA 19104. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1528-9117
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corresponding to potential cells of origin: germinal center B-cellYlike (GCB), activated B-cellYlike (ABC), and primary mediastinal large B-cell lymphoma (PMBL) with approximately 15% of cases remaining unclassifiable.3,4 The clinical significance of these gene signatures lies in their ability to prognosticate, with GCB-DLBCLs having a significantly more favorable overall survival than the ABC cases.4 Interestingly, PMBL not only clusters as a distinct entity with a more favorable prognosis than either DLBCL subtype, but also displays a GEP closely related to that of classic Hodgkin lymphoma.5 Unfortunately, over a decade later, GEP is still not routinely available in the clinical setting, although some potential exists.6 As such, numerous immunohistochemical surrogates and algorithms have been devised in an attempt to recapitulate this classification using markers including CD10, BCL6, MUM1, BCL2, LMO2, GCET1, and FOXP1.7Y11 Although clinically accessible, these algorithms are fraught with reproducibility issues. Although at best they show 80% to 93% concordance with GEP classification, reports conflict widely on their clinical applicability.7Y12 Indeed, some have even questioned the added value of GEP analyses themselves.13 Other GEP analyses have demonstrated subgroups of DLBCL based on the biology of the lymphoma cells and the host response including the stromal microenvironment, which may be useful in identifying pathways critical for targeted therapies.14,15 Incorporation of immunohistochemical markers of the microenvironment, such as SPARC and CD31, may improve prognostication.16
STRUCTURAL GENETIC ABERRATIONS AND SINGLE-GENE APPROACHES Based on karyotyping and fluorescence in situ hybridization data, single-gene approaches have been applied to the categorization of DLBCL. Several recurrent translocations occur in DLBCL, often involving IGH at 14q32. Frequent translocation partners for IGH include BCL6 at 3q27 (È35%), BCL2 at 18q21 (È25%), and MYC at 8q24 (È10%).17 BCL6 translocations are the most common structural aberrations seen in DLBCL and occur more commonly in the ABC subtype.1,18Y21 BCL6 is a transcriptional repressor expressed in germinal center B cells that normally controls a broad spectrum of genes, including those involved in B-cell receptor signalling, response to DNA damage (e.g., TP53), and plasma cell differentiation (e.g., BLIMP1).18Y21 Thus, the oncogenic effect of deregulated BCL6 expression is primarily the result of a loss of normal pathways of B-cell differentiation and abnormal DNA damage repair.20 Mutations of BCL6, which cluster in the same 5¶ regulatory region as the translocations, reflect it being targeted by somatic hypermutation in germinal center B cells.20 Aberrant somatic hypermutation also affects other genes implicated in oncogenesis of DLBCL including MYC, PAX5, PIM1, PIM2, SOCS1, BACH2, CIITA, and TCL1A.22 Although more widely recognized in association with follicular lymphoma, translocations involving the BCL2 gene are common in de novo DLBCL, as well as those evolving from follicular lymphoma. BCL2, an antiapoptotic protein, plays a critical role in normal B-cell development, especially within the www.journalppo.com
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germinal center. Not surprisingly, the (14;18)(q32;q21) is more common in DLBCL with a GCB phenotype.23 In contrast, fluorescence in situ hybridization studies have demonstrated gains of the BCL2 gene in up to 40% of cases of nonYGCBDLBCL.24 These differing mechanisms for BCL2 overexpression may in part explain the somewhat confusing data regarding the prognosis of BCL2 in DLBCL.25 Initially, it was proposed that BCL2 expression was associated with poor outcomes in DLBCL in general.26 Subsequently, it was shown that it only had prognostic relevance in ABC-DLBCL (but not GCB-DLBCL) in the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) era.27 Most recently, with the addition of rituximab to CHOP, the opposite has been demonstrated, with this adverse association largely been restricted to GCB-DLBCL.28Y30 Translocations involving MYC alone occur in a wide spectrum of large B-cell lymphomas, including a subset of DLBCL NOS without distinctive morphologic or immunophenotypic features. MYC translocation in DLBCL is associated with poor outcomes even in the setting of aggressive therapy and stem cell transplant.31,32 MYC translocations in DLBCL may occur together with BCL2 (and/or BCL6) translocations, leading to both inhibition of apoptosis (via BCL2 overexpression) and promotion of cell growth and proliferation (via MYC overexpression). These ‘‘double-hit’’ DLBCLs often have features that overlap between conventional DLBCL and Burkitt lymphoma (intermediate sized cells, high proliferation index), and they have an extremely poor prognosis, making detection of these aberrations critical.33 Importantly, double-hit DLBCLs are not synonymous with the World Health Organization category of B-cell lymphoma unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. Recent studies suggest that BCL2 and MYC protein coexpression, detected via immunohistochemistry, in DLBCL predicts prognosis more accurately than the double genetic hits do.30,34Y36 Thus, testing for both genetic aberrations involving BCL2 and MYC, as well as protein expression via immunohistochemistry, may be warranted for prognostication in DLBCL. Recently, translocations involving IRF4 (MUM1) have been described in 5% of DLBCL cases and correlate with younger age and a favorable prognosis.37 The t(6;14)(p25;q32) is cytogenetically cryptic and translocates IRF4 next to IGH. A recently described capture sequencing strategy has identified yet other novel IGH translocation partners such as IL-8, APRIL (TNFRSF13), and EBF1.38
MASSIVELY PARALLEL SEQUENCING Massively parallel sequencing has further unraveled the genomic heterogeneity among DLBCLs and is beginning to elicit a wealth of data with regard to the pathways and mutations that drive these diseases.39Y42 In many cases, these studies support the distinction between GCB and ABC-DLBCL established by GEP, and highlight single genes and pathways critical to the pathogenesis of each (Table 1). Mutations in genes involved in the nuclear factor JB (NF-JB) and B-cell receptor signaling pathways (e.g., TNFAIP3, CD79B, CARD11, MYD88, PRDM1/ BLIMP1) are common in ABC-DLBCLs, whereas mutations in genes involved in histone methylation (e.g., MLL2, EZH2, CREBBP) are more frequently seen among GCB cases.39Y45 Recurrent mutations in GNAI2, GNA13, and S1PR2, which are involved in Rho-mediated B-cell migration, are enriched in GCB-DLBCLs.41 In addition to confirming the biologic difference between the 2 subgroups, sequencing studies have added to our understanding of the overall landscape of mutations in DLBCL in several ways. For example, genes encoding proteins involved in
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immunosurveillance such as B2M, CD58, TNFSF9, TNFRSF14, and CIITA have also been discovered. In addition, mutations in the tumor suppressor TP53 have been confirmed, occurring in È20% of DLBCL, most commonly in the DNA binding domain. In the era of R-CHOP (rituximab-CHOP) therapy, these mutations have been shown to predict poor prognosis in both ABC and GCB-DLBCL, although monoallelic deletions and loss of heterozygosity have no affect on prognosis.46,47 Recent studies have identified TP53 single-nucleotide variations within the 3¶ untranslated region that alter transcription levels of p53 and affect prognosis, especially in tumors with coding sequence TP53 mutations.48
IMPLICATIONS FOR THERAPY Current conventional therapy for DLBCL (R-CHOP) produces durable remission in only È60% of patients. The search for novel, less cytotoxic, and targeted therapeutic agents is ongoing and is accelerating due to the recent wealth of emerging pathogenetic information. For example, trials using inhibitors of the NF-JB pathway, such as bortezomib, have shown efficacy in patients with relapsed DLBCL. The response rate to bortezomib plus chemotherapy was higher in ABC-DLBCL, than GCBDLBCL with improved median overall survival, supporting the critical role of NF-JB pathway activation in ABC-DLBCL.25,49 Chemotherapy-naive DLBCLs might also benefit from the addition of bortezomib, although these results are preliminary.50 Fostamatinib, an Syk inhibitor, and ibrutinib, a BTK inhibitor, as well as other small molecule inhibitors, target portions of the B-cell receptor signaling pathway and have shown efficacy in early studies of relapsed/refractory DLBCL.51,52 These would be expected to preferentially target ABC-DLBCL due to dependence on BCR signaling in this subtype. Although the overall response rate to ibrutinib in a phase 2 trial was only 23%, as predicted, there was a marked skewing of responders in the ABC subgroup (41% response vs. 5% in GCB group).53 For the GCB-DLBCL, agents targeting BCL2 might be of clinical utility because BCL2 overexpression confers a poor outcome following R-CHOP in this subtype but not in ABCDLBCL.54 In addition, cases with EZH2 mutations, which are found exclusively in the GCB subtype, may benefit from therapy targeting this protein.55 As noted, some GEP panels stratify DLBCL based primarily on the stromal composition.15 Thus, it has been proposed that subtypes with higher blood vessel density may respond favorably to antiangiogenic agents such as lenalidomide and antiYvascular endothelial growth factor agents. However, clinical trials invesitgating the antiYvascular endothelial growth factor monoclonal antibody, bevacixumab, were not promising and showed high toxicity.56 Lenalidomide, however, which shows additional activity as an NF-JB inhibitor, has shown efficacy in conjunction with chemotherapy in clinical trials for both relapsed and untreated DLBCL and may preferentially benefit ABCDLBCLs.57,58 Finally, novel agents such as chimeric antigen receptorYmodified T cells with specificity for CD19, which have shown efficacy in both chronic lymphocytic leukemia and B lymphoblastic leukemia,59,60 may very well prove useful in DLBCL, which is typically CD19 positive.61
CONCLUSIONS Although a diagnosis of DLBCL in 2013 typically does not rely on molecular or cytogenetic data, the ability of routine histopathologic and immunophenotyping data to predict prognosis or guide therapy in this disease is limited. Rapid advances in molecular technology have vastly expanded our knowledge of the genetics that underlie DLBCL. It is evident that no single * 2014 Lippincott Williams & Wilkins
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t(14;18)/BCL2 (È40%) mCREBBP (È40%) mMLL2 (È30%) mGNA13 (È30%) mEZH2 (È20%) amp MIR17-92 (È15%) j10q23/PTEN (È10%) t(3;3)/TBL1XR1-TP63 (È5%) j1p/TP73(È25%) +2p/REL (È15%) +12q12/CDK2, CDK4 (È10%) t(6;14)/IRF4 (young adults) (È5%) mS1PR2 (È5%) mGNAI2 j1p36/CDK11A* mDPYD* mCSMD3* mIL9R*
t(3q27)/BCL6 (È45%) +18q21-22/BCL2 (È35%) j9p/CDKN2A (È30%) mBLIMP1 (È30%) mMYD88 (È30%) j6q21-22/BLIMP1 (È25%) +19q/SPIB (È25%) mTNFAIP3 (È25%) mCD79B (È20%) mBCL6 (È20%) mCARD11 (È10%) +3/?FOXP1 (È10%) mTMSL3 (È10%)* mP2RY8 (È10%)*
mPCLO (È35%)* mPIM1 (È30%)* mB2M (È30%) mTP53 (È20%) mMEF2B (È20%)* mTNFRSF14 (È20%)* t(8q24)/MYC (È15%) mHIST1H1C (È15%)* mBTG1 (È15%)* mTET2 (È10%)* mFOXO1 (È10%) mCD58 (È10%)
Both ABC and GCB
+9p/JAK2, PDL1, PDL2, JMJD2C (È45%) mSOCS1 (È45%) t(16p13)/CIITA (È35%) mSTAT6 (È35%) mTNFAIP3 (È35%) +2p/REL, BCL11A (È20%)
PMBL
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Some genetic lesions more commonly occur in either the GCB or ABC subgroups, whereas others are independent of cell of origin (COO). *Indicates genetic events have been described in DLBCL but not yet investigated based on COO.39,41,62,63 m Indicates mutation; amp, amplification.
Key genetic events
ABC
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GCB
TABLE 1. Recurrent Critical Genetic Events in DLBCL
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gene or mutation is responsible for this heterogeneous disease. In fact, it is clear that not only multiple genes, but also multiple types of mutations within those genes, and the downstream effects of combinations of mutations are relevant, and thus ‘‘targeted therapy’’ in DLBCL is more rationally directed at cellular pathways rather than specific genes. The accessibility of molecular testing, especially massively parallel sequencing, in the clinical laboratory will soon enable routine testing of DLBCL for known mutation targets. As with other nascent technologies, the data yielded from these studies will be complex and require integration with other cytogenetic, molecular, and histopathologic data by an expert hematopathologist equipped to curate the therapeutically and prognostically relevant data. The ideal pathology report will then provide not only a diagnosis of DLBCL, but also a specific profile of the molecular biology underlying that DLBCL, which will then translate into patient-specific therapies and prognostic information. REFERENCES 1. Swerdlow S, Campo E, Harris N, et al,, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. 2. Coiffier B, Lepage E, Briere J. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235Y242. 3. Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403: 503Y511. 4. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937Y1947. 5. Rosenwald A, Wright G, Leroy K. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851Y862. 6. Barrans SL, Crouch S, Care MA, et al. Whole genome expression profiling based on paraffin embedded tissue can be used to classify diffuse large B-cell lymphoma and predict clinical outcome. Br J Haematol. 2012;159:441Y453. 7. de Jong D, Xie W, Rosenwald A, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium). J Clin Pathol. 2009;62: 128Y138. 8. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy [published online ahead of print August 27, 2009]. Clin Cancer Res. 2009;15:5494Y5502. 9. Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275Y282. 10. Meyer PN, Fu K, Greiner TC. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol. 2011;29:200Y207. 11. Visco C, Li Y, Xu-Monette ZY. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26: 2103Y2113. 12. Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117:4836Y4843.
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Genetics of Diffuse Large B-Cell Lymphoma Paving a Path to Personalized Medicine Rebecca L. King, MD,* and Adam Bagg, MDÞ
Abstract: Diffuse large B-cell lymphoma, the most common type of lymphoma in Western countries, remains incurable in approximately 40% of patients. Over the past decade, nascent molecular technologies have led to the discovery of many of the genetic events underlying the pathogenesis of this group of diseases. Whether by defining gene signatures that subclassify diffuse large B-cell lymphoma into subgroups, dysregulation of key cellular pathways, or specific mutations, we are approaching an era in which personalized diagnostics, prognostication, and therapy are imminent. Key Words: Diffuse large B-cell lymphoma, personalized diagnostics, nascent molecular technologies (Cancer J 2014;20: 43Y47)
A
lthough the most recent publication of the World Health Organization classification acknowledges several distinct variants and subtypes of diffuse large B-cell lymphoma (DLBCL), primarily based on morphologic and clinical features, the vast majority of cases fall under the DLBCL, not otherwise specified (DLBCL NOS) category. Although this classification scheme simplifies the diagnosis of such lymphomas for the pathologist, it unsurprisingly results in a heterogeneous group of tumors with much clinical variation. The earliest attempts to subclassify DLBCL NOS (referred to as DLBCL in this review) were focused on the cytopathologic features of either centroblastic or immunoblastic large B cells.1 In addition to cytopathology, the anatomic site of presentation may, in some cases, predict clinical behavior and thus has become the basis for many of the subclasses of DLBCL. Although the addition over a decade ago of the anti-CD20 monoclonal antibody, rituximab, to multiagent chemotherapy markedly improved outcomes in DLBCL, 30% to 40% of patients continue to demonstrate suboptimal responses to therapy.2 This underscores the need for better prognostic and predictive markers, as well as potential therapeutic targets, and has fueled prolific investigation into the genetic basis of DLBCL. This review summarizes the wealth of literature on the molecular pathogenesis of DLBCL focusing on attempts to define clinically relevant subsets of disease and novel therapeutic targets.
GENE EXPRESSION PROFILING In the early 2000s, gene expression profiling (GEP) using microarrays provided much insight into the biologic heterogeneity of DLBCL. Early studies identified distinct signatures From the *Perelman School of Medicine at the University of Pennsylvania, The Children’s Hospital of Philadelphia; and †Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA. Reprints: Adam Bagg, MD, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 7.103 Founders Pavilion, 3400 Spruce St, Philadelphia, PA 19104. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1528-9117
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corresponding to potential cells of origin: germinal center B-cellYlike (GCB), activated B-cellYlike (ABC), and primary mediastinal large B-cell lymphoma (PMBL) with approximately 15% of cases remaining unclassifiable.3,4 The clinical significance of these gene signatures lies in their ability to prognosticate, with GCB-DLBCLs having a significantly more favorable overall survival than the ABC cases.4 Interestingly, PMBL not only clusters as a distinct entity with a more favorable prognosis than either DLBCL subtype, but also displays a GEP closely related to that of classic Hodgkin lymphoma.5 Unfortunately, over a decade later, GEP is still not routinely available in the clinical setting, although some potential exists.6 As such, numerous immunohistochemical surrogates and algorithms have been devised in an attempt to recapitulate this classification using markers including CD10, BCL6, MUM1, BCL2, LMO2, GCET1, and FOXP1.7Y11 Although clinically accessible, these algorithms are fraught with reproducibility issues. Although at best they show 80% to 93% concordance with GEP classification, reports conflict widely on their clinical applicability.7Y12 Indeed, some have even questioned the added value of GEP analyses themselves.13 Other GEP analyses have demonstrated subgroups of DLBCL based on the biology of the lymphoma cells and the host response including the stromal microenvironment, which may be useful in identifying pathways critical for targeted therapies.14,15 Incorporation of immunohistochemical markers of the microenvironment, such as SPARC and CD31, may improve prognostication.16
STRUCTURAL GENETIC ABERRATIONS AND SINGLE-GENE APPROACHES Based on karyotyping and fluorescence in situ hybridization data, single-gene approaches have been applied to the categorization of DLBCL. Several recurrent translocations occur in DLBCL, often involving IGH at 14q32. Frequent translocation partners for IGH include BCL6 at 3q27 (È35%), BCL2 at 18q21 (È25%), and MYC at 8q24 (È10%).17 BCL6 translocations are the most common structural aberrations seen in DLBCL and occur more commonly in the ABC subtype.1,18Y21 BCL6 is a transcriptional repressor expressed in germinal center B cells that normally controls a broad spectrum of genes, including those involved in B-cell receptor signalling, response to DNA damage (e.g., TP53), and plasma cell differentiation (e.g., BLIMP1).18Y21 Thus, the oncogenic effect of deregulated BCL6 expression is primarily the result of a loss of normal pathways of B-cell differentiation and abnormal DNA damage repair.20 Mutations of BCL6, which cluster in the same 5¶ regulatory region as the translocations, reflect it being targeted by somatic hypermutation in germinal center B cells.20 Aberrant somatic hypermutation also affects other genes implicated in oncogenesis of DLBCL including MYC, PAX5, PIM1, PIM2, SOCS1, BACH2, CIITA, and TCL1A.22 Although more widely recognized in association with follicular lymphoma, translocations involving the BCL2 gene are common in de novo DLBCL, as well as those evolving from follicular lymphoma. BCL2, an antiapoptotic protein, plays a critical role in normal B-cell development, especially within the www.journalppo.com
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germinal center. Not surprisingly, the (14;18)(q32;q21) is more common in DLBCL with a GCB phenotype.23 In contrast, fluorescence in situ hybridization studies have demonstrated gains of the BCL2 gene in up to 40% of cases of nonYGCBDLBCL.24 These differing mechanisms for BCL2 overexpression may in part explain the somewhat confusing data regarding the prognosis of BCL2 in DLBCL.25 Initially, it was proposed that BCL2 expression was associated with poor outcomes in DLBCL in general.26 Subsequently, it was shown that it only had prognostic relevance in ABC-DLBCL (but not GCB-DLBCL) in the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) era.27 Most recently, with the addition of rituximab to CHOP, the opposite has been demonstrated, with this adverse association largely been restricted to GCB-DLBCL.28Y30 Translocations involving MYC alone occur in a wide spectrum of large B-cell lymphomas, including a subset of DLBCL NOS without distinctive morphologic or immunophenotypic features. MYC translocation in DLBCL is associated with poor outcomes even in the setting of aggressive therapy and stem cell transplant.31,32 MYC translocations in DLBCL may occur together with BCL2 (and/or BCL6) translocations, leading to both inhibition of apoptosis (via BCL2 overexpression) and promotion of cell growth and proliferation (via MYC overexpression). These ‘‘double-hit’’ DLBCLs often have features that overlap between conventional DLBCL and Burkitt lymphoma (intermediate sized cells, high proliferation index), and they have an extremely poor prognosis, making detection of these aberrations critical.33 Importantly, double-hit DLBCLs are not synonymous with the World Health Organization category of B-cell lymphoma unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. Recent studies suggest that BCL2 and MYC protein coexpression, detected via immunohistochemistry, in DLBCL predicts prognosis more accurately than the double genetic hits do.30,34Y36 Thus, testing for both genetic aberrations involving BCL2 and MYC, as well as protein expression via immunohistochemistry, may be warranted for prognostication in DLBCL. Recently, translocations involving IRF4 (MUM1) have been described in 5% of DLBCL cases and correlate with younger age and a favorable prognosis.37 The t(6;14)(p25;q32) is cytogenetically cryptic and translocates IRF4 next to IGH. A recently described capture sequencing strategy has identified yet other novel IGH translocation partners such as IL-8, APRIL (TNFRSF13), and EBF1.38
MASSIVELY PARALLEL SEQUENCING Massively parallel sequencing has further unraveled the genomic heterogeneity among DLBCLs and is beginning to elicit a wealth of data with regard to the pathways and mutations that drive these diseases.39Y42 In many cases, these studies support the distinction between GCB and ABC-DLBCL established by GEP, and highlight single genes and pathways critical to the pathogenesis of each (Table 1). Mutations in genes involved in the nuclear factor JB (NF-JB) and B-cell receptor signaling pathways (e.g., TNFAIP3, CD79B, CARD11, MYD88, PRDM1/ BLIMP1) are common in ABC-DLBCLs, whereas mutations in genes involved in histone methylation (e.g., MLL2, EZH2, CREBBP) are more frequently seen among GCB cases.39Y45 Recurrent mutations in GNAI2, GNA13, and S1PR2, which are involved in Rho-mediated B-cell migration, are enriched in GCB-DLBCLs.41 In addition to confirming the biologic difference between the 2 subgroups, sequencing studies have added to our understanding of the overall landscape of mutations in DLBCL in several ways. For example, genes encoding proteins involved in
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immunosurveillance such as B2M, CD58, TNFSF9, TNFRSF14, and CIITA have also been discovered. In addition, mutations in the tumor suppressor TP53 have been confirmed, occurring in È20% of DLBCL, most commonly in the DNA binding domain. In the era of R-CHOP (rituximab-CHOP) therapy, these mutations have been shown to predict poor prognosis in both ABC and GCB-DLBCL, although monoallelic deletions and loss of heterozygosity have no affect on prognosis.46,47 Recent studies have identified TP53 single-nucleotide variations within the 3¶ untranslated region that alter transcription levels of p53 and affect prognosis, especially in tumors with coding sequence TP53 mutations.48
IMPLICATIONS FOR THERAPY Current conventional therapy for DLBCL (R-CHOP) produces durable remission in only È60% of patients. The search for novel, less cytotoxic, and targeted therapeutic agents is ongoing and is accelerating due to the recent wealth of emerging pathogenetic information. For example, trials using inhibitors of the NF-JB pathway, such as bortezomib, have shown efficacy in patients with relapsed DLBCL. The response rate to bortezomib plus chemotherapy was higher in ABC-DLBCL, than GCBDLBCL with improved median overall survival, supporting the critical role of NF-JB pathway activation in ABC-DLBCL.25,49 Chemotherapy-naive DLBCLs might also benefit from the addition of bortezomib, although these results are preliminary.50 Fostamatinib, an Syk inhibitor, and ibrutinib, a BTK inhibitor, as well as other small molecule inhibitors, target portions of the B-cell receptor signaling pathway and have shown efficacy in early studies of relapsed/refractory DLBCL.51,52 These would be expected to preferentially target ABC-DLBCL due to dependence on BCR signaling in this subtype. Although the overall response rate to ibrutinib in a phase 2 trial was only 23%, as predicted, there was a marked skewing of responders in the ABC subgroup (41% response vs. 5% in GCB group).53 For the GCB-DLBCL, agents targeting BCL2 might be of clinical utility because BCL2 overexpression confers a poor outcome following R-CHOP in this subtype but not in ABCDLBCL.54 In addition, cases with EZH2 mutations, which are found exclusively in the GCB subtype, may benefit from therapy targeting this protein.55 As noted, some GEP panels stratify DLBCL based primarily on the stromal composition.15 Thus, it has been proposed that subtypes with higher blood vessel density may respond favorably to antiangiogenic agents such as lenalidomide and antiYvascular endothelial growth factor agents. However, clinical trials invesitgating the antiYvascular endothelial growth factor monoclonal antibody, bevacixumab, were not promising and showed high toxicity.56 Lenalidomide, however, which shows additional activity as an NF-JB inhibitor, has shown efficacy in conjunction with chemotherapy in clinical trials for both relapsed and untreated DLBCL and may preferentially benefit ABCDLBCLs.57,58 Finally, novel agents such as chimeric antigen receptorYmodified T cells with specificity for CD19, which have shown efficacy in both chronic lymphocytic leukemia and B lymphoblastic leukemia,59,60 may very well prove useful in DLBCL, which is typically CD19 positive.61
CONCLUSIONS Although a diagnosis of DLBCL in 2013 typically does not rely on molecular or cytogenetic data, the ability of routine histopathologic and immunophenotyping data to predict prognosis or guide therapy in this disease is limited. Rapid advances in molecular technology have vastly expanded our knowledge of the genetics that underlie DLBCL. It is evident that no single * 2014 Lippincott Williams & Wilkins
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t(14;18)/BCL2 (È40%) mCREBBP (È40%) mMLL2 (È30%) mGNA13 (È30%) mEZH2 (È20%) amp MIR17-92 (È15%) j10q23/PTEN (È10%) t(3;3)/TBL1XR1-TP63 (È5%) j1p/TP73(È25%) +2p/REL (È15%) +12q12/CDK2, CDK4 (È10%) t(6;14)/IRF4 (young adults) (È5%) mS1PR2 (È5%) mGNAI2 j1p36/CDK11A* mDPYD* mCSMD3* mIL9R*
t(3q27)/BCL6 (È45%) +18q21-22/BCL2 (È35%) j9p/CDKN2A (È30%) mBLIMP1 (È30%) mMYD88 (È30%) j6q21-22/BLIMP1 (È25%) +19q/SPIB (È25%) mTNFAIP3 (È25%) mCD79B (È20%) mBCL6 (È20%) mCARD11 (È10%) +3/?FOXP1 (È10%) mTMSL3 (È10%)* mP2RY8 (È10%)*
mPCLO (È35%)* mPIM1 (È30%)* mB2M (È30%) mTP53 (È20%) mMEF2B (È20%)* mTNFRSF14 (È20%)* t(8q24)/MYC (È15%) mHIST1H1C (È15%)* mBTG1 (È15%)* mTET2 (È10%)* mFOXO1 (È10%) mCD58 (È10%)
Both ABC and GCB
+9p/JAK2, PDL1, PDL2, JMJD2C (È45%) mSOCS1 (È45%) t(16p13)/CIITA (È35%) mSTAT6 (È35%) mTNFAIP3 (È35%) +2p/REL, BCL11A (È20%)
PMBL
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Some genetic lesions more commonly occur in either the GCB or ABC subgroups, whereas others are independent of cell of origin (COO). *Indicates genetic events have been described in DLBCL but not yet investigated based on COO.39,41,62,63 m Indicates mutation; amp, amplification.
Key genetic events
ABC
&
GCB
TABLE 1. Recurrent Critical Genetic Events in DLBCL
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gene or mutation is responsible for this heterogeneous disease. In fact, it is clear that not only multiple genes, but also multiple types of mutations within those genes, and the downstream effects of combinations of mutations are relevant, and thus ‘‘targeted therapy’’ in DLBCL is more rationally directed at cellular pathways rather than specific genes. The accessibility of molecular testing, especially massively parallel sequencing, in the clinical laboratory will soon enable routine testing of DLBCL for known mutation targets. As with other nascent technologies, the data yielded from these studies will be complex and require integration with other cytogenetic, molecular, and histopathologic data by an expert hematopathologist equipped to curate the therapeutically and prognostically relevant data. The ideal pathology report will then provide not only a diagnosis of DLBCL, but also a specific profile of the molecular biology underlying that DLBCL, which will then translate into patient-specific therapies and prognostic information. REFERENCES 1. Swerdlow S, Campo E, Harris N, et al,, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. 2. Coiffier B, Lepage E, Briere J. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235Y242. 3. Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403: 503Y511. 4. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937Y1947. 5. Rosenwald A, Wright G, Leroy K. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851Y862. 6. Barrans SL, Crouch S, Care MA, et al. Whole genome expression profiling based on paraffin embedded tissue can be used to classify diffuse large B-cell lymphoma and predict clinical outcome. Br J Haematol. 2012;159:441Y453. 7. de Jong D, Xie W, Rosenwald A, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium). J Clin Pathol. 2009;62: 128Y138. 8. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy [published online ahead of print August 27, 2009]. Clin Cancer Res. 2009;15:5494Y5502. 9. Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275Y282. 10. Meyer PN, Fu K, Greiner TC. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol. 2011;29:200Y207. 11. Visco C, Li Y, Xu-Monette ZY. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26: 2103Y2113. 12. Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117:4836Y4843.
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