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  • Review Article
  • Published:

Precision therapy for lymphoma—current state and future directions

Nature Reviews Clinical Oncology volume 11, pages 585–596 (2014)Cite this article

Subjects

Key Points

  • Lymphomas exhibit heterogeneous genomic alterations, both across and within histological subtypes

  • The molecular heterogeneity underlying lymphoma accounts, at least in part, for variable responses to treatment

  • Lymphoma investigators should incorporate biomarkers into clinical trials to facilitate the clinical development of molecularly targeted therapeutics

  • Techniques for identifying and reporting genomic alterations must be optimized and standardized so that mechanism-based therapies can be effectively applied to the clinical care of lymphoma patients

Abstract

Modern advances in genomics and cancer biology have produced an unprecedented body of knowledge regarding the molecular pathogenesis of lymphoma. The diverse histological subtypes of lymphoma are molecularly heterogeneous, and most likely arise from distinct oncogenic mechanisms. In parallel to these advances in lymphoma biology, several new classes of molecularly targeted agents have been developed with varying degrees of efficacy across the different types of lymphoma. In general, the development of new drugs for treating lymphoma has been mostly empiric, with a limited knowledge of the molecular target, its involvement in the disease, and the effect of the drug on the target. Thus, the variability observed in clinical responses likely results from underlying molecular heterogeneity. In the era of personalized medicine, the challenge for the treatment of patients with lymphoma will involve correctly matching a molecularly targeted therapy to the unique genetic and molecular composition of each individual lymphoma. In this Review, we discuss current and emerging biomarkers that can guide treatment decisions for patients with lymphoma, and explore the potential challenges and strategies for making biomarker-driven personalized medicine a reality in the cure and management of this disease.

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Figure 1: Example of positive selection of patients likely to respond to targeted therapy.
Figure 2: Example of negative selection of patients likely to be resistant to targeted therapy.
Figure 3: Basket trials may facilitate drug development for cancers with low frequency driver mutations.
Figure 4: Developing rational combination therapies based on biological knowledge.

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References

  1. International Agency for Research on Cancer. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 [online], (2012).

  2. Campo, E. et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117, 5019–5032 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shankland, K. R., Armitage, J. O. & Hancock, B. W. Non-Hodgkin lymphoma. Lancet 380, 848–857 (2012).

    Article  PubMed  Google Scholar 

  4. Vose, J. et al. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J. Clin. Oncol. 26, 4124–4130 (2008).

    Article  PubMed  Google Scholar 

  5. Roschewski, M., Staudt, L. M. & Wilson, W. H. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat. Rev. Clin. Oncol. 11, 12–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Borchmann, P., Eichenauer, D. A. & Engert, A. State of the art in the treatment of Hodgkin lymphoma. Nat. Rev. Clin. Oncol. 9, 450–459 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Ng, A. K., LaCasce, A. & Travis, L. B. Long-term complications of lymphoma and its treatment. J. Clin. Oncol. 29, 1885–1892 (2011).

    Article  PubMed  Google Scholar 

  8. Younes, A. Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat. Rev. Clin. Oncol. 8, 85–96 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Coiffier, B. et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116, 2040–2045 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Habermann, T. M. et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J. Clin. Oncol. 24, 3121–3127 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Pfreundschuh, M. et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 9, 105–116 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Rosenwald, A. et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favourable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198, 851–862 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002).

    Article  PubMed  Google Scholar 

  15. Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Dave, S. S. et al. Molecular diagnosis of Burkitt's lymphoma. N. Engl. J. Med. 354, 2431–2442 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Dave, S. S. et al. Prediction of survival in follicular lymphoma based on molecular features of tumour-infiltrating immune cells. N. Engl. J. Med. 351, 2159–2169 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Rosenwald, A. et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3, 185–197 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-kappa B in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Wilson, W. H. et al. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicentre, open-label, phase 2 study [abstract]. Blood 120, a686 (2012).

    Google Scholar 

  25. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43, 830–837 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 110, 1398–1403 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nat. Genet. 44, 1321–1325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Richter, J. et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat. Genet. 44, 1316–1320 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep. 6, 130–140 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bea, S. et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl Acad. Sci. USA 110, 18250–18255 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kridel, R. et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119, 1963–1971 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Rossi, D. et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J. Exp. Med. 209, 1537–1551 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kiel, M. J. et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J. Exp. Med. 209, 1553–1565 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yoo, H. Y. et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sakata-Yanagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Yap, D. B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-centre origin. Nat. Genet. 42, 181–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Challa-Malladi, M. et al. Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20, 728–740 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ying, C. Y. et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat. Immunol. 14, 1084–1092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Trinh, D. L. et al. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood 121, 3666–3674 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shaffer, A. L. 3rd, Young, R. M. & Staudt, L. M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tanigaki, K. et al. Notch-RBP-J signalling is involved in cell fate determination of marginal zone B cells. Nat. Immunol. 3, 443–450 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11, 685–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Dewey, F. E. et al. Clinical interpretation and implications of whole-genome sequencing. JAMA 311, 1035–1045 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, Q. et al. Detecting somatic point mutations in cancer genome sequencing data: a comparison of mutation callers. Genome Med. 5, 91 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Morin, R. D. et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122, 1256–1265 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Intlekofer, A. M. et al. Profiling genomic alterations of diffuse large B-cell lymphoma (DLBCL) at diagnosis, relapse, and transformation, using a novel clinical diagnostic targeted sequencing platform [abstract]. Blood 122, a1761 (2013).

    Article  CAS  Google Scholar 

  55. Chin, L., Hahn, W. C., Getz, G. & Meyerson, M. Making sense of cancer genomic data. Genes Dev. 25, 534–555 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Stamatoyannopoulos, J. A. et al. Human mutation rate associated with DNA replication timing. Nat. Genet. 41, 393–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wagle, N. et al. High-throughput detection of actionable genomic alterations in clinical tumour samples by targeted, massively parallel sequencing. Cancer Discov. 2, 82–93 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023–1031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hodges, E. et al. Hybrid selection of discrete genomic intervals on custom-designed microarrays for massively parallel sequencing. Nat. Protoc. 4, 960–974 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182–189 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lipson, D. et al. Identification of actionable genomic alterations in haematologic malignancies by a clinical next generation sequencing-based assay [abstract]. Blood 122, a230 (2013).

    Google Scholar 

  65. Younes, A. & Berry, D. A. From drug discovery to biomarker-driven clinical trials in lymphoma. Nat. Rev. Clin. Oncol. 9, 643–653 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chi, P., Allis, C. D. & Wang, G. G. Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32, 606–613 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Lane, A. A. & Chabner, B. A. Histone deacetylase inhibitors in cancer therapy. J. Clin. Oncol. 27, 5459–5468 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Beguelin, W. et al. EZH2 is required for germinal centre formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumour-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Qi, W. et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumour cells proliferation. Proc. Natl Acad. Sci. USA 109, 21360–21365 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  75. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  76. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  77. Cairns, R. A. et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119, 1901–1903 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair haematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, C. et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev. 27, 1974–1985 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gopal, A. K. et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rahal, R. et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat. Med. 20, 87–92 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Senftleben, U. et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signalling pathway. Science 293, 1495–1499 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Young, R. M. & Staudt, L. M. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat. Rev. Drug Discov. 12, 229–243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Landau, D. A. et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152, 714–726 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gerlinger, M. et al. Intratumour heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Burrell, R. A., McGranahan, N., Bartek, J. & Swanton, C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501, 338–345 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cheson, B. D. & Leonard, J. P. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N. Engl. J. Med. 359, 613–626 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Green, T. 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. 30, 3460–3467 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Johnson, N. A. et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J. Clin. Oncol. 30, 3452–3459 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hu, S. 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 121, 4021–4031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Huang, X. et al. Activation of the STAT3 signalling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. J. Clin. Oncol. 31, 4520–4528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kluk, M. J. et al. Gauging NOTCH1 activation in cancer using immunohistochemistry. PLoS ONE 8, e67306 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bose, S., Chandran, S., Mirocha, J. M. & Bose, N. The Akt pathway in human breast cancer: a tissue-array-based analysis. Mod. Pathol. 19, 238–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Espinosa, I. et al. Activation of the NF-kappaB signalling pathway in diffuse large B-cell lymphoma: clinical implications. Histopathology 53, 441–449 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Mengel, M. et al. Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J. Pathol. 198, 292–299 (2002).

    Article  PubMed  Google Scholar 

  105. Taylor, C. R. & Levenson, R. M. Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment II. Histopathology 49, 411–424 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Walker, R. A. Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment I. Histopathology 49, 406–410 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Smith, N. R. & Womack, C. A matrix approach to guide IHC-based tissue biomarker development in oncology drug discovery. J. Pathol. 232, 190–198 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Rikova, K. et al. Global survey of phosphotyrosine signalling identifies oncogenic kinases in lung cancer. Cell 131, 1190–1203 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Olsen, J. V. et al. Global, in vivo, and site-specific phosphorylation dynamics in signalling networks. Cell 127, 635–648 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Rush, J. et al. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat. Biotechnol. 23, 94–101 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Pasqualucci, L. & Dalla-Favera, R. SnapShot: diffuse large B cell lymphoma. Cancer Cell 25, 132–132.e1 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Wagle, N. et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4, 546–553 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Voss, M. H. et al. Tumour genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin. Cancer Res. 20, 1955–1964 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sleijfer, S., Bogaerts, J. & Siu, L. L. Designing transformative clinical trials in the cancer genome era. J. Clin. Oncol. 31, 1834–1841 (2013).

    Article  PubMed  Google Scholar 

  116. Cheson, B. D. et al. Revised response criteria for malignant lymphoma. J. Clin. Oncol. 25, 579–586 (2007).

    Article  PubMed  Google Scholar 

  117. Milowsky, M. I. et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 112, 462–470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Phrma. Medicines in Development for Cancer [online], (Accessed July 2014).

  120. Mathews Griner, L. A. et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc. Natl Acad. Sci. USA 111, 2349–2354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Oki, Y. et al. Phase I Study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin. Cancer Res. 19, 6882–6890 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dang, C. et al. Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhoea. J. Clin. Oncol. 28, 2982–2988 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014).

    Article  PubMed  Google Scholar 

  124. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  PubMed  Google Scholar 

  125. McDonnell, T. J. et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57, 79–88 (1989).

    Article  CAS  PubMed  Google Scholar 

  126. McDonnell, T. J. & Korsmeyer, S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 349, 254–256 (1991).

    Article  CAS  PubMed  Google Scholar 

  127. Strasser, A., Harris, A. W., Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).

    Article  CAS  PubMed  Google Scholar 

  128. Fanidi, A., Harrington, E. A. & Evan, G. I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 359, 554–556 (1992).

    Article  CAS  PubMed  Google Scholar 

  129. Bissonnette, R. P., Echeverri, F., Mahboubi, A. & Green, D. R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359, 552–554 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Vandenberg, C. J. & Cory, S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood 121, 2285–2288 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumour activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Sander, S. et al. Synergy between PI3K signalling and MYC in Burkitt lymphomagenesis. Cancer Cell 22, 167–179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

A.M.I. would like to thank the Conquer Cancer Foundation of ASCO for funding.

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Authors and Affiliations

  1. Lymphoma Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 330, New York, 10065, NY, USA

    Andrew M. Intlekofer & Anas Younes

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  1. Andrew M. Intlekofer
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A.M.I. and A.Y. researched data for article, reviewed and edited the manuscript before submission, substantially contributed to discussion of content and wrote the manuscript.

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Correspondence to Anas Younes.

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A.M.I. and A.Y. have served as consultants for Foundation Medicine

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Intlekofer, A., Younes, A. Precision therapy for lymphoma—current state and future directions. Nat Rev Clin Oncol 11, 585–596 (2014). https://doi.org/10.1038/nrclinonc.2014.137

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