Diagnostic and predictive biomarkers for lymphoma diagnosis and treatment in the era of precision medicine

Modern Pathology (2016) 29, 1118–1142 1118 © 2016 USCAP, Inc All rights reserved 0893-3952/16 $32.00 Diagnostic and predictive biomarkers for lymphoma diagnosis and treatment in the era of precision medicine Ruifang Sun1,2, L Jeffrey Medeiros1 and Ken H Young1,3 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology, Shanxi Cancer Hospital, Shanxi, China and 3The University of Texas Graduate School of Biomedical Science, Houston, TX, USA Lymphomas are a group of hematological malignancies derived from lymphocytes. Lymphomas are clinically and biologically heterogeneous and have overlapping diagnostic features. With the advance of new technologies and the application of efficient and feasible detection platforms, an unprecedented number of novel biomarkers have been discovered or are under investigation at the genetic, epigenetic, and protein level as well as the tumor microenvironment. These biomarkers have enabled new clinical and pathological insights into the mechanisms underlying lymphomagenesis and also have facilitated improvements in the diagnostic workup, sub-classification, outcome stratification, and personalized therapy for lymphoma patients. However, integrating these biomarkers into clinical practice effectively and precisely in daily practice is challenging. More in-depth studies are required to further validate these novel biomarkers and to assess other parameters that can affect the reproducibility of these biomarkers such as the selection of detection methods, biological reagents, interpretation of data, and cost efficiency. Despite these challenges, there are many reasons to be optimistic that novel biomarkers will facilitate better algorithms and strategies as we enter a new era of precision medicine to better refine diagnosis, prognostication, and rational treatment design for patients with lymphomas. Modern Pathology (2016) 29, 1118–1142; doi:10.1038/modpathol.2016.92; published online 1 July 2016 Lymphomas are a group of hematological malignancies that are derived from lymphocytes and occur predominantly in lymph nodes or other lymphoid structures. More than 50 different types of lymphoma were described in the 2008 World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues.1 Lymphomas are heterogeneous at the clinical, morphological, and molecular level, and have overlapping features. Mechanistic studies have shown that lymphomas are driven or affected by abnormal genetic alterations, disordered epigenetic regulation, aberrant pathway activation, and complex tumor–microenvironment interactions.2–4 Hence, the diagnosis and classification of different lymphomas and related entities can be challenging. In addition, the molecular heterogeneity underlying lymphoma aggressiveness and progression leads to patients who are treated similarly having variable outcomes.5–7 Although biomarkers, especially protein markers detected mainly by immunohistochemistry and flow cytometry, have been used widely and have contributed greatly to diagnosis, classification, and prognostication of lymphomas, novel clinically applicable, reliable, and reproducible biomarkers for lymphoma diagnosis and prognosis are still needed for better supervision of clinical trials. In this review, we summarize biomarkers that are related to alterations in lymphomas at the genetic, epigenetic, and protein level as well as the tumor microenvironment. We mainly concentrate on the diagnostic and prognostic value of these biomarkers in the most common types of lymphoma. Correspondence: Dr KH Young, MD, PhD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77230-1439, USA. E-mail: Received 18 January 2016; revised 13 April 2016; accepted 14 April 2016; published online 1 July 2016 Genomic aberrations and relevant dysregulated oncogenic regulatory pathways account for many malignant phenotypes in lymphomagenesis.4,8 With the wide application of advanced technologies, the identification of genetic alterations and related biomarkers has become available.4 Microarray-based Biomarkers of genetic alterations www.modernpathology.org Diagnostic and predictive biomarkers in lymphomas 1119 R Sun et al Figure 1 Schematic representation of B-cell development and summary of molecular and immunophenotypic biomarkers in B-cell nonHodgkin lymphomas and Hodgkin lymphomas. The GC is an important structure during B-cell differentiation (black arrows direct the B-cell development). Most types of B-cell lymphoma are proposed to be derived from GC or post-GC B cells (purple arrows indicate the proposed cellular origin of B-cell lymphomas). FL, BL, and GCB-DLBCL are of GC origin, whereas ABC-DLBCL, PMBL, and cHL are inferred to be post-GC origin. MCL is thought to be derived from the mantle zone. Certain molecular features are relatively specific for given type of lymphoma and have diagnostic or prognostic potential. Recurrent gain of function (red) and loss of function (blue) molecular biomarkers of common types of B-cell lymphoma and HLs are summarized. Immunohistochemical biomarkers (green) that are of diagnostic value in B-cell lymphomas are also shown. ABC-DLBCL, activated B-cell-DLBCL; BL, Burkitt lymphoma; cHL, classical Hodgkin lymphoma; FDC, follicular dendritic cell; FL, follicular lymphoma; GCB-DLBCL, GC B-cell-like diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; PMBCL, primary mediastinal B-cell lymphoma; TFH, T follicular helper cell. technologies like gene expression profiling and massively parallel sequencing technologies like next-generation sequencing have enabled the discovery of novel biomarkers and the exploration of underlying molecular mechanisms of lymphomagenesis;2,9 these findings also support better diagnosis and stratification of patients who may benefit from potential therapeutic strategies based on targeting specific alterations. Figures 1 and 2 summarize recurrent genomic and molecular biomarkers involved in B-cell, T-cell, and natural killer (NK) cell lymphomas. The prognostic effects of genetic abnormalities of MYC, BCL2, BCL6, and TP53 in diffuse large B-cell lymphoma are also presented using a large cohort data set in Figure 3.10–13 B-Cell Lymphoma 6 (BCL6) BCL6 encodes a transcriptional factor that has a key role in germinal center B-cell differentiation and in the pathogenesis of germinal center-derived lymphomas. Translocation and mutation are the most common means by which BCL6 activity is dysregulated.14,15 Both rearrangement and somatic mutation of BCL6 can be present simultaneously in diffuse large B-cell lymphoma, but somatic mutations occur independently of BCL6 rearrangement. Studies in vitro and in animal models have shown that aberrant Bcl-6 expression results mainly from BCL6 translocation.16,17 High expression of BCL6 mRNA and protein have been shown to be associated (...truncated)