Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas
Abstract
:1. Classification
2. Gene Expression Profiling
2.1. Cell of Origin (COO)
2.2. Key Genes
3. Tissue Microenvironment (TME)
4. Genetic Classification
4.1. Whole-Exome Sequencing (WES)-Based Studies
4.2. Targeted NGS and Bioinformatic-Based Studies
5. Open Issues and Perspectives
Funding
Acknowledgments
Conflicts of Interest
References
- Swerdlow, S.H.; Campo, E.; Harris, N.L.; Jaffe, E.S.; Pileri, S.A.; Stein, H.; Thiele, J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th ed.; International Agency for Research on Cancer: Lyon, France, 2017; p. 2. [Google Scholar]
- Harris, N.L.; Jaffe, E.S.; Stein, H.; Banks, P.M.; Chan, J.K.; Cleary, M.L.; Delsol, G.; De Wolf-Peeters, C.; Falini, B.; Gatter, K.C.; et al. A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994, 84, 1361–1392. [Google Scholar] [CrossRef] [Green Version]
- Jaffe, E.S.; Harris, N.L.; Stein, H.; Vardiman, J. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues; IARC Press: Lyon, France, 2001. [Google Scholar]
- Swerdlow, S.H.; Campo, E.; Harris, N.L.; Jaffe, E.S.; Pileri, S.A.; Stein, H.; Thiele, J.; Vardiman, J.W. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed.; International Agency for Research on Cancer: Lyon, France, 2008. [Google Scholar]
- Fisher, R.I.; Gaynor, E.R.; Dahlberg, S.; Oken, M.M.; Grogan, T.M.; Mize, E.M.; Glick, J.H.; Coltman, C.A.; Miller, T.P. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N. Engl. J. Med. 1993, 328, 1002–1006. [Google Scholar] [CrossRef]
- Harrysson, S.; Eloranta, S.; Ekberg, S.; Enblad, G.; Jerkeman, M.; Wahlin, B.E.; Andersson, P.-O.; Smedby, K.E. Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden. Blood Cancer J. 2021, 11, 9. [Google Scholar] [CrossRef] [PubMed]
- Sehn, L.H.; Salles, G. Diffuse large B-cell lymphoma. N. Engl. J. Med. 2021, 384, 842–858. [Google Scholar] [CrossRef]
- Alizadeh, A.A.; Eisen, M.B.; Davis, R.E.; Ma, C.; Lossos, I.S.; Rosenwald, A.; Boldrick, J.C.; Sabet, H.; Tran, T.; Yu, X.; et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nat. Cell Biol. 2000, 403, 503–511. [Google Scholar] [CrossRef] [PubMed]
- Rosenwald, A.; Wright, G.; Chan, W.C.; Connors, J.M.; Campo, E.; Fisher, R.I.; Gascoyne, R.D.; Muller-Hermelink, H.K.; Smeland, E.B.; Giltnane, J.M.; et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002, 346, 1937–1947. [Google Scholar] [CrossRef] [PubMed]
- Nyman, H.; Jerkeman, M.; Karjalainen-Lindsberg, M.-L.; Banham, A.H.; Leppä, S. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod. Pathol. 2009, 22, 1094–1101. [Google Scholar] [CrossRef]
- Wright, G.; Tan, B.; Rosenwald, A.; Hurt, E.H.; Wiestner, A.; Staudt, L.M. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA 2003, 100, 9991–9996. [Google Scholar] [CrossRef] [Green Version]
- Hans, C.P.; Weisenburger, D.D.; Greiner, T.C.; Gascoyne, R.D.; Delabie, J.; Ott, G.; Müller-Hermelink, H.K.; Campo, E.; Braziel, R.M.; Jaffe, E.S.; et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004, 103, 275–282. [Google Scholar] [CrossRef]
- Choi, W.W.L.; Weisenburger, D.D.; Greiner, T.C.; Piris, M.A.; Banham, A.H.; Delabie, J.; Braziel, R.M.; Geng, H.; Iqbal, J.; Lenz, G.; et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin. Cancer Res. 2009, 15, 5494–5502. [Google Scholar] [CrossRef] [Green Version]
- Colomo, L.; López-Guillermo, A.; Perales, M.; Rives, S.; Martínez, A.; Bosch, F.; Colomer, D.; Falini, B.; Montserrat, E.; Campo, E.; et al. Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood 2003, 101, 78–84. [Google Scholar] [CrossRef]
- Muris, J.J.F.; Meijer, C.J.L.M.; Vos, W.; Van Krieken, J.H.J.M.; Jiwa, N.M.; Ossenkoppele, G.J.; Oudejans, J.J. Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J. Pathol. 2006, 208, 714–723. [Google Scholar] [CrossRef] [PubMed]
- Meyer, P.N.; Fu, K.; Greiner, T.C.; Smith, L.M.; Delabie, J.; Gascoyne, R.D.; Ott, G.; Rosenwald, A.; Braziel, R.M.; Campo, E.; et al. 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, 200–207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zinzani, P.L.; Dirnhofer, S.; Sabattini, E.; Alinari, L.; Piccaluga, P.P.; Stefoni, V.; Tani, M.; Musuraca, G.; Marchi, E.; Falini, B.; et al. Identification of outcome predictors in diffuse large B-cell lymphoma. Immunohistochemical profiling of homogeneously treated de novo tumors with nodal presentation on tissue micro-arrays. Haematologica 2005, 90, 341–347. [Google Scholar] [PubMed]
- Visco, C.; Li, Y.; Xu-Monette, Z.Y.; Miranda, R.N.; Green, T.M.; Li, Y.; Tzankov, A.; Wen, W.; Liu, W.-m.; Kahl, B.S.; et al. 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, 2103–2113. [Google Scholar] [CrossRef] [PubMed]
- de Jong, D.; Rosenwald, A.; Chhanabhai, M.; Gaulard, P.; Klapper, W.; Lee, A.; Sander, B.; Thorns, C.; Campo, E.; Molina, T.; 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. Oncol. 2007, 25, 805–812. [Google Scholar] [CrossRef] [PubMed]
- Gutiérrez-García, G.; Cardesa-Salzmann, T.; Climent, F.; González-Barca, E.; Mercadal, S.; Mate, J.L.; Sancho, J.M.; Arenillas, L.; Serrano, S.; Escoda, L.; et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood 2011, 117, 4836–4843. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scott, D.W.; Wright, G.W.; Williams, P.M.; Lih, C.-J.; Walsh, W.; Jaffe, E.S.; Rosenwald, A.; Campo, E.; Chan, W.C.; Connors, J.M.; et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 2014, 123, 1214–1217. [Google Scholar] [CrossRef] [PubMed]
- Scott, D.W.; Mottok, A.; Ennishi, D.; Wright, G.W.; Farinha, P.; Ben-Neriah, S.; Kridel, R.; Barry, G.S.; Hother, C.; Abrisqueta, P.; et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J. Clin. Oncol. 2015, 33, 2848–2856. [Google Scholar] [CrossRef]
- Jais, J.P.; Molina, T.J.; Ruminy, P.; Gentien, D.; Reyes, C.; Scott, D.W.; Rimsza, L.M.; Wright, G.; Gascoyne, R.D.; Staudt, L.M.; et al. Reliable subtype classification of diffuse large B-cell lymphoma samples from GELA LNH2003 trials using the Lymph2Cx gene expression assay. Haematologica 2017, 102, e404–e406. [Google Scholar] [CrossRef] [Green Version]
- Gifford, G.; Gabrielli, S.; Gill, A.; Greenwood, M.; Wong, K.; Best, G.; Nevell, D.; Mcllroy, K.; Kliman, D.; Ilmay-Gillespie, L.; et al. Lymphoma cell-of-origin assignment by gene expression profiling is clinically meaningful across broad laboratory contexts. Br. J. Haematol. 2018, 181, 272–275. [Google Scholar] [CrossRef] [Green Version]
- Derenzini, E.; Mazzara, S.; Melle, F.; Motta, G.; Fabbri, M.; Bruna, R.; Agostinelli, C.; Cesano, A.; Corsini, C.A.; Chen, N.; et al. A 3-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma. Haematologica 2020. Online ahead of Print. [Google Scholar] [CrossRef]
- Staiger, A.M.; Ziepert, M.; Horn, H.; Scott, D.W.; Barth, T.F.E.; Bernd, H.-W.; Feller, A.C.; Klapper, W.; Szczepanowski, M.; Hummel, M.; et al. Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the german high-grade non-Hodgkin’s lymphoma study group. J. Clin. Oncol. 2017, 35, 2515–2526. [Google Scholar] [CrossRef]
- Vitolo, U.; Trněný, M.; Belada, D.; Burke, J.M.; Carella, A.M.; Chua, N.; Abrisqueta, P.; Demeter, J.; Flinn, I.; Hong, X.; et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J. Clin. Oncol. 2017, 35, 3529–3537. [Google Scholar] [CrossRef]
- Vitolo, U.; Witzig, T.E.; Gascoyne, R.D.; Scott, D.W.; Zhang, Q.; Jurczak, W.; Özcan, M.; Hong, X.; Zhu, J.; Jin, J.; et al. ROBUST: First report of phase III randomized study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Hematol. Oncol. 2019, 37, 36–37. [Google Scholar] [CrossRef] [Green Version]
- Green, T.M.; Young, K.H.; Visco, C.; Xu-Monette, Z.Y.; Orazi, A.; Go, R.S.; Nielsen, O.; Gadeberg, O.V.; Mourits-Andersen, T.; Frederiksen, M.; et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J. Clin. Oncol. 2012, 30, 3460–3467. [Google Scholar] [CrossRef]
- Hu, S.; Xu-Monette, Z.Y.; Tzankov, A.; Green, T.; Wu, L.; Balasubramanyam, A.; Liu, W.; Visco, C.; Li, Y.; Miranda, R.N.; et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: A report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 2013, 121, 4021–4031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ziepert, M.; Lazzi, S.; Santi, R.; Vergoni, F.; Granai, M.; Mancini, V.; Staiger, A.; Horn, H.; Löffler, M.; Pöschel, V.; et al. A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients. Haematologica 2020, 105, 2667–2670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, W.C. Using gene expression profiling to move beyond MYC/BCL2 rearrangements in high-grade lymphoma. J. Clin. Oncol. 2019, 37, 175–177. [Google Scholar] [CrossRef]
- Sha, C.; Barrans, S.; Cucco, F.; Bentley, M.A.; Care, M.A.; Cummin, T.; Kennedy, H.; Thompson, J.S.; Uddin, R.; Worrillow, L.; et al. Molecular high-grade B-cell lymphoma: Defining a poor-risk group that requires different approaches to therapy. J. Clin. Oncol. 2019, 37, 202–212. [Google Scholar] [CrossRef] [PubMed]
- Ennishi, D.; Jiang, A.; Boyle, M.; Collinge, B.; Grande, B.M.; Ben-Neriah, S.; Rushton, C.; Tang, J.; Thomas, N.; Slack, G.W.; et al. Double-hit gene expression signature defines a distinct sub-group of germinal center B-cell-like diffuse large B-cell lymphoma. J. Clin. Oncol. 2019, 37, 190–201. [Google Scholar] [CrossRef]
- Jost, P.J.; Ruland, J. Aberrant NF-kappaB signaling in lymphoma: Mechanisms, consequences, and therapeutic implications. Blood 2007, 109, 2700–2707. [Google Scholar] [CrossRef] [Green Version]
- Davies, A.; Cummin, T.E.; Barrans, S.; Maishman, T.; Mamot, C.; Novak, U.; Caddy, J.; Stanton, L.; Kazmi-Stokes, S.; McMillan, A.; et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): An open label, randomised, phase 3 trial. Lancet Oncol. 2019, 20, 649–662. [Google Scholar] [CrossRef] [Green Version]
- Bu, R.; Hussain, A.R.; Al-Obaisi, K.A.S.; Ahmed, M.; Uddin, S.; Al-Kuraya, K.S. Bortezomib inhibits proteasomal degradation of IκBα and induces mitochondrial dependent apoptosis in activated B-cell diffuse large B-cell lymphoma. Leuk. Lymphoma 2014, 55, 415–424. [Google Scholar] [CrossRef] [PubMed]
- Mottok, A.; Wright, G.; Rosenwald, A.; Ott, G.; Ramsower, C.; Campo, E.; Braziel, R.M.; Delabie, J.; Weisenburger, D.D.; Song, J.Y.; et al. Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens. Blood 2018, 132, 2401–2405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lenz, G.; Wright, G.; Dave, S.S.; Xiao, W.; Powell, J.; Zhao, H.; Xu, W.; Tan, B.; Goldschmidt, N.; Iqbal, J.; et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 2008, 359, 2313–2323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alizadeh, A.A.; Gentles, A.J.; Alencar, A.J.; Liu, C.L.; Kohrt, H.E.; Houot, R.; Goldstein, M.J.; Zhao, S.; Natkunam, Y.; Advani, R.H.; et al. Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. Blood 2011, 118, 1350–1358. [Google Scholar] [CrossRef] [PubMed]
- Meyer, P.N.; Fu, K.; Greiner, T.; Smith, L.; Delabie, J.; Gascoyne, R.; Ott, G.; Rosenwald, A.; Braziel, R.; Campo, E.; et al. The stromal cell marker SPARC predicts for survival in patients with diffuse large B-cell lymphoma treated with rituximab. Am. J. Clin. Pathol. 2011, 135, 54–61. [Google Scholar] [CrossRef] [Green Version]
- Keane, C.; Gill, D.; Vari, F.; Cross, D.; Griffiths, L.; Gandhi, M. CD4+ tumor infiltrating lymphocytes are prognostic and independent of RIPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am. J. Hematol. 2013, 88, 273–276. [Google Scholar] [CrossRef] [Green Version]
- Abdou, A.G.; Asaad, N.; Kandil, M.; Shabaan, M.; Shams, A. Significance of stromal-1 and stromal-2 signatures and biologic prognostic model in diffuse large B-cell lymphoma. Cancer Biol. Med. 2017, 14, 151–161. [Google Scholar] [CrossRef] [Green Version]
- Ciavarella, S.; Vegliante, M.C.; Fabbri, M.; De Summa, S.; Melle, F.; Motta, G.; De Iuliis, V.; Opinto, G.; Enjuanes, A.; Rega, S.; et al. Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue. Ann. Oncol. 2018, 29, 2363–2370. [Google Scholar] [CrossRef] [Green Version]
- Staiger, A.M.; Altenbuchinger, M.; Ziepert, M.; Kohler, C.; Horn, H.; Huttner, M.; Hüttl, K.S.; Glehr, G.; Klapper, W.; Szczepanoswki, M.; et al. Emed Demonstrator Project; German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL): A novel lymphoma-associated macrophage interaction signature (LAMIS) provides robust risk prognostication in diffuse large B-cell lymphoma clinical trial cohorts of the DSHNHL. Leukemia 2020, 34, 543–552. [Google Scholar] [CrossRef]
- Tripodo, C.; Zanardi, F.; Iannelli, F.; Mazzara, S.; Vegliante, M.; Morello, G.; Di Napoli, A.; Mangogna, A.; Facchetti, F.; Sangaletti, S.; et al. A spatially resolved dark-versus light-zone microenvironment signature subdivides germinal center-related aggressive B cell lymphomas. iScience 2020, 23, 101562. [Google Scholar] [CrossRef]
- Ennishi, D.; Takata, K.; Béguelin, W.; Duns, G.; Mottok, A.; Farinha, P.; Bashashati, A.; Saberi, S.; Boyle, M.; Meissner, B.; et al. Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition. Cancer Discov. 2019, 9, 546–563. [Google Scholar] [CrossRef] [Green Version]
- Kotlov, N.; Bagaev, A.; Revuelta, M.V.; Phillip, J.M.; Cacciapuoti, M.T.; Antysheva, Z.; Svekolkin, V.; Tikhonova, E.; Miheecheva, N.; Kuzkina, N.; et al. Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures. Cancer Discov 2021. Online ahead of Print. [Google Scholar] [CrossRef] [PubMed]
- Reddy, A.; Zhang, J.; Davis, N.S.; Moffitt, A.B.; Love, C.L.; Waldrop, A.; Leppa, S.; Pasanen, A.; Meriranta, L.; Karjalainen-Lindsberg, M.L.; et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell 2017, 171, 481–494.e15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bolen, C.R.; Klanova, M.; Trneny, M.; Sehn, L.H.; He, J.; Tong, J.; Paulson, J.N.; Kim, E.; Vitolo, U.; Di Rocco, A.; et al. Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: Data from the phase III GOYA study. Haematologica 2019, 105, 2298–2307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chapuy, B.; Stewart, C.; Dunford, A.J.; Kim, J.; Kamburov, A.; Redd, R.A.; Lawrence, M.S.; Roemer, M.G.M.; Li, A.J.; Ziepert, M.; et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat. Med. 2018, 24, 679–690. [Google Scholar] [CrossRef] [PubMed]
- Schmitz, R.; Wright, G.W.; Huang, D.W.; Johnson, C.A.; Phelan, J.D.; Wang, J.Q.; Roulland, S.; Kasbekar, M.; Young, R.M.; Shaffer, A.L.; et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 2018, 378, 1396–1407. [Google Scholar] [CrossRef]
- Xu-Monette, Z.Y.; Wu, L.; Visco, C.; Tai, Y.C.; Tzankov, A.; Liu, W.-M.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: Report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood 2012, 120, 3986–3996. [Google Scholar] [CrossRef]
- Lacy, S.E.; Barrans, S.L.; Beer, P.A.; Painter, D.; Smith, A.G.; Roman, E.; Cooke, S.L.; Ruiz, C.; Glover, P.; Van Hoppe, S.J.L.; et al. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: A Haematological Malignancy Research Network report. Blood 2020, 135, 1759–1771. [Google Scholar] [CrossRef] [PubMed]
- Ennishi, D.; Healy, S.; Bashashati, A.; Saberi, S.; Hother, C.; Mottok, A.; Chan, F.C.; Chong, L.; Abraham, L.; Kridel, R.; et al. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma. Nat. Med. 2020, 26, 577–588. [Google Scholar] [CrossRef] [PubMed]
- Wright, G.W.; Huang, D.W.; Phelan, J.D.; Coulibaly, Z.A.; Roulland, S.; Young, R.M.; Wang, J.Q.; Schmitz, R.; Morin, R.D.; Tang, J.; et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell 2020, 37, 551–568.e14. [Google Scholar] [CrossRef] [PubMed]
- Morin, R.D.; Scott, D.W. DLBCL subclassification: Divide and conquer? Blood 2020, 135, 1722–1724. [Google Scholar] [CrossRef]
- Tabanelli, V.; Melle, F.; Motta, G.; Mazzara, S.; Fabbri, M.; Corsini, C.; Gerbino, E.; Calleri, A.; Sapienza, M.R.; Abbene, I.; et al. Evolutionary crossroads: Morphological heterogeneity reflects divergent intra-clonal evolution in a case of high-grade B-cell lymphoma. Haematologica 2020, 105, e432–e436. [Google Scholar] [CrossRef]
- Scherer, F.; Kurtz, D.M.; Newman, A.M.; Stehr, H.; Craig, A.F.M.; Esfahani, M.S.; Lovejoy, A.F.; Chabon, J.J.; Klass, D.M.; Liu, C.L.; et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci. Transl. Med. 2016, 8, 364ra155. [Google Scholar] [CrossRef] [Green Version]
- Rossi, D.; Diop, F.; Spaccarotella, E.; Monti, S.; Zanni, M.; Rasi, S.; Deambrogi, C.; Spina, V.; Bruscaggin, A.; Favini, C.; et al. Diffuse large B-cell lymphoma genotyping on the liquid biopsy. Blood 2017, 129, 1947–1957. [Google Scholar] [CrossRef] [PubMed]
- Kurtz, D.M.; Esfahani, M.S.; Scherer, F.; Soo, J.; Jin, M.C.; Liu, C.L.; Newman, A.M.; Dührsen, U.; Hüttmann, A.; Casasnovas, O.; et al. Dynamic risk profiling using serial tumor biomarkers for personalized outcome prediction. Cell 2019, 178, 699–713.e19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Diffuse Large B-Cell Lymphoma (DLBCL): |
DLBCL not otherwise specified (NOS) |
Morphological variants |
Centroblastic |
Immunoblastic |
Anaplastic |
Other rare variants |
Molecular subtypes |
Germinal centre B-cell subtype (GCB) |
Activated B-cell subtype (ABC) |
Other lymphomas of Large B-Cells: |
T-cell/histiocyte-rich large B-cell lymphoma |
Primary DLBCL of the CNS |
Primary cutaneous DLBCL, leg type |
EBV-positive DLBCL, NOS |
EBV-positive mucocutaneous ulcer |
DLBCL associated with chronic inflammation |
Lymphomatoid granulomatosis |
Large B-cell lymphoma with IRF4 rearrangement |
Primary mediastinal (thymic) large B-cell lymphoma |
Intravascular large B-cell lymphoma |
ALK-positive large B-cell lymphoma |
Plasmablastic lymphoma |
HHV8-positive DLBCL |
Primary effusion lymphoma |
High-Grade B-Cell Lymphoma: |
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement |
High-grade B-cell lymphoma, not otherwise specified (NOS) |
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin’s lymphoma |
Lacy et al. | Chapuy et al. | Schmitz et al. | Notes | ||||
---|---|---|---|---|---|---|---|
MYD88 | | C5 | | MCD | | MYD88 | Strongly associated with ABC. The most robust group in all reports. Contains the most primary PCNSL and testicular lymphoma. Poor prognosis. |
CD79B | |||||||
PIM1 | |||||||
ETV6 | |||||||
CDKN2A | |||||||
TBL1XR1 | |||||||
BCL2 | | C3 | | EZB | | EZH2 | Strongly associated with GCB. Contains most transformed FLs and cases with a concurrent FL. Generally favorable prognosis, although enriched for cases of double-hit lymphoma and MHG. |
BCL2 | |||||||
BCL2 translocation | |||||||
KMT2D | |||||||
TNFRSF14 | |||||||
CREBBP | |||||||
CREBBP2 | |||||||
SOCS1/SGK1 | | C4 | | | CD83 | Predominantly GCB. Shares genetic and gene expression features of PMBCL. Associated with the most favorable prognosis. | |
HIST1H1E | |||||||
SGK1 | |||||||
NFKBIA | |||||||
NFKBIE | |||||||
SOCS1 | |||||||
BRAF | |||||||
TET2/SGK1 | | | | TET2 | A less strongly identifiable subtype. Has very strong similarity to SOCS1/SGK1 but differs by the addition of TET2 and BRAF and the lack of SOCS1 and CD83. Favorable prognosis. | ||
BRAF | |||||||
SGK1 | |||||||
KLHL6 | |||||||
ID3 | |||||||
NOTCH2 | | C1 | | BN2 | | BCL10 | Not associated with any COO. Shares mutational similarity to MZL but not enriched for transformed MZLs. Less strongly defined than other subgroups. |
TNFAIP3 | |||||||
NOTCH2 | |||||||
BCL6 translocation | |||||||
CCND3 | |||||||
SPEN | |||||||
UBE2A | |||||||
CD70 | |||||||
NEC | | | Other | | NOTCH1 | A default category, containing cases that could not be classified elsewhere and no detected mutation. Likely to also contain cases belonging to both NOTCH1 and TP53/CNA subgroups. | |
REL amplification | |||||||
TP53 | |||||||
| C2 | | | TP53 | Characterized by TP53 mutation and widespread copy number changes. | ||
Frequent deletions | |||||||
| C0 | | | No detected abnormalities | Cases with no detectable mutation were allocated to the NEC group. | ||
| | N1 | | NOTCH1 | Characterized by NOTCH1 mutation, this was significantly elevated in Lacy’s NEC group but only mutated in 2.5% of samples. Associated with poor outcome. |
Genetics | GEP Signature | Related LNH | Targets | 5y-OS | ||
---|---|---|---|---|---|---|
| MCD | My-T-BCR dependent NF-kB; Immune evasion-MHC class I; Cell survival; BCL2 expression; Altered B-cell differentiation; G1-S cell cycle/p53 checkpoint; BCR: IgM >> IgG; IgVH 4-34++ | B-cell activation NF-kB IRF4 MYC Proliferation | Primary extranodal DLBCL Transformed WM | BCR-dep. NF-kB PI3K mTORC1 BCL2-BCLXL-MCL1 JAK1 IRAK4 IRF4 | 40% All 37% ABC |
| N1 | NOTCH1 signaling Altered B cell differentiation BCR: IgM > IgG | NOTCH Quiescence Plasma cells T cell-Myeloid-FDC | NOTCH1 mutated CLL | NOTCH1 Immune checkpoints | 27% All 22% ABC |
| A53 | TP53 inactivation—DNA Damage Aneuploidy Immune evasion—B2M loss BCR: IgM >> IgG; IgVH 4-34++ | p53 Immune low | - | BCR-dep. NF-kB | 63% All 33% ABC 100% GCB |
| BN2 | NOTCH2 signaling Altered B cell differentiation BCR-dependent NF-kB Immune evasion—CD70 loss Proliferation—Cyclin D3 BCR: IgM >> IgG; IgVH 4-34++ | B-cell activation NF-kB NOTCH Proliferation | MZL Transformed MZL | BCR-dep. NF-kB PI3K mTORC1 BCL2 NOTCH2 | 67% All 76% ABC 100% GCB 38% UC |
| ST2 | JAK/STAT3 signaling NF-kB activation P2RY8-GNA13 activation Altered B cell differentiation BCR: IgM >> IgG | GC B cell PI3K signaling JAK2 signaling Glycolysis Stromal | NLPHL THRLBCL | PI3K JAK2 | 84% All 81% GCB |
| MYC+ | Chromatin modification Anti-apoptosis PI3K signaling S1PR2-GNA13 inactivation Altered TFH interactions MYC (EZ-MYC+) BCR: IgG > IgM | GC LZ (MYC−) GC IZ (MYC+) BCL6 (MYC+) TCF3 (both) TFH cells (MYC−) Stromal (MYC−) Immune low (MYC+) | FL Transformed FL BL (EZB-MYC+) | PI3K mTORC1 EZH2 BCL2-MCL1 | 48% MYC+ 82% MYC− |
MYC− |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Pileri, S.A.; Tripodo, C.; Melle, F.; Motta, G.; Tabanelli, V.; Fiori, S.; Vegliante, M.C.; Mazzara, S.; Ciavarella, S.; Derenzini, E. Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas. Cells 2021, 10, 675. https://doi.org/10.3390/cells10030675
Pileri SA, Tripodo C, Melle F, Motta G, Tabanelli V, Fiori S, Vegliante MC, Mazzara S, Ciavarella S, Derenzini E. Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas. Cells. 2021; 10(3):675. https://doi.org/10.3390/cells10030675
Chicago/Turabian StylePileri, Stefano A., Claudio Tripodo, Federica Melle, Giovanna Motta, Valentina Tabanelli, Stefano Fiori, Maria Carmela Vegliante, Saveria Mazzara, Sabino Ciavarella, and Enrico Derenzini. 2021. "Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas" Cells 10, no. 3: 675. https://doi.org/10.3390/cells10030675