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Supplementary Table S1. Sanger validated variants. Supplementary Table S2. Mutations in HSTL driver genes. Supplementary Table S3. Other mutations identified by exome sequencing. Supplementary Table S4. Copy number of HSTL patients and cell lines. Supplementary Table S5. Clinical and pathological characteristics of HSTL patients. Supplementary Tables S6, S7. Comparison to HSTL clinical data in the literature. Supplementary Table S8. Mutational frequencies in other lymphomas. Supplementary Table S9. HSTL mutations in other lymphoma driver genes. Supplementary Table S10. Gene set enrichment analysis of DERL2 SETD2 shRNA.

Supplementary Figure S1. Sanger sequencing chromatograms. Supplementary Figure S2. Cancer cell fraction for driver genes. Supplementary Figure S3. Ideogram with chromosome 7 alterations. Supplementary Figure S4. Examples of Exome Copy Number. Supplementary Figure S5. Exploratory Kaplan-Meier plots for clinical covariates. Supplementary Figure S6. Exploratory Kaplan-Meier plots for molecular covariates. Supplementary Figure S7. Sanger and exome sequencing validation of SETD2 biallelic mutation in one HSTL case. Supplementary Figure S8. SETD2 expression in mutant vs. wildtype cases. Supplementary Figure S9. Mutual exclusivity of STAT5B, PIK3CD, and STAT3 mutations.

PDF file - 57KB, Supplemental Table 1. Genes differently expressed in EBV+ DLBCL vs. EBV-negative DLBCL. A. Genes upregulated in EBV+ DLBCL; B. Genes downregulated in EBV+ DLBCL

PDF file - 3781KB, Supplemental Figure 1. Morphologic subtypes of EBV+ DLBCL. A, E, I, and M. The monomorphic subtype is composed of monotonous sheets of large transformed B-cells. B, F, J and N. The polymorphic subtype, canonical large B-cell neoplasm variant contains high density of large neoplastic cells and scattered cells with HRS-like features. C, G, K and O. The polymorphic subtype, Hodgkin-like variant shows lower density of neoplastic cells with HRS-like features. D, H, L and P. The polymorphic subtype, lymphoproliferative disorder-like variant has low density of neoplastic cells without Hodgkin lymphoma-like features. By immunohistochemistry, the monomorphic variant had a GCB phenotype, but all 3 polymorphic variants showed non-GCB phenotype.

Purpose: Epstein–Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries.Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).Results: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative (EBV−) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV+ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV− DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV+ DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.Conclusions: The clinical characteristics of patients with EBV+ versus EBV− DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338–49. ©2014 AACR.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369–79. ©2017 AACR. See related commentary by Yoshida and Weinstock, p. 352. This article is highlighted in the In This Issue feature, p. 339

// Zijun Y. Xu-Monette 1,* , Meifeng Tu 2,* , Kausar J. Jabbar 1 , Xin Cao 1 , Alexandar Tzankov 3 , Carlo Visco 4 , Qingqing Cai 1 , Santiago Montes-Moreno 5 , Yuji An 1 , Karen Dybkaer 6 , April Chiu 7 , Attilio Orazi 8 , Youli Zu 9 , Govind Bhagat 10 , Kristy L. Richards 11 , Eric D. Hsi 12 , William W.L. Choi 13 , J. Han van Krieken 14 , Jooryung Huh 15 , Maurilio Ponzoni 16 , Andres J.M. Ferreri 16 , Xiaoying Zhao 17 , Michael B. Moller 18 , John P. Farnen 19 , Jane N. Winter 20 , Miguel A. Piris 5 , Roberto N. Miranda 1 , L. Jeffrey Medeiros 1 and Ken H. Young 1,21 1 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Peking University Cancer Hospital and Institute, Beijing, China 3 University Hospital, Basel, Switzerland 4 San Bortolo Hospital, Vicenza, Italy 5 Hospital Universitario Marques de Valdecilla, Santander, Spain 6 Aalborg University Hospital, Aalborg, Denmark 7 Memorial Sloan-Kettering Cancer Center, New York, NY, USA 8 Weill Medical College of Cornell University, New York, NY, USA 9 The Methodist Hospital, Houston, TX, USA 10 Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA 11 University of North Carolina School of Medicine, Chapel Hill, NC, USA 12 Cleveland Clinic, Cleveland, OH, USA 13 University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China 14 Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands 15 Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea 16 San Raffaele H. Scientific Institute, Milan, Italy 17 Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China 18 Odense University Hospital, Odense, Denmark 19 Gundersen Lutheran Health System, La Crosse, WI, USA 20 Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 21 The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas, USA * These authors made equal contributions to this work Correspondence to: Ken H. Young, email: // Keywords : ABC, BCL2, CD5, diffuse large B-cell lymphoma, NF-κB Received : December 29, 2014 Accepted : January 02, 2015 Published : March 08, 2015 Abstract CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5 + DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5 + DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell–like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5 + DLBCL patients had significantly worse overall survival (median, 25.3 months vs . not reached, P < .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P < .0001) than CD5 – DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression abolished the prognostic significance of CD5 expression, suggesting a tumor-suppressor role of SSBP2 for CD5 signaling. Gene-expression profiling demonstrated that B-cell receptor signaling dysfunction and microenvironment alterations are the important mechanisms underlying the clinical impact of CD5 expression. This study shows the distinctive clinical and biological features of CD5 + DLBCL patients in Western countries and underscores important pathways with therapeutic implications.

Overseas Chinese business networks have been a powerful growth engine propelling local economies in Southeast Asia and the Greater China region. However, relatively little research has been conducted on the relationship between social capital and a firm's synergy creation in overseas Chinese business networks. To narrow this knowledge gap, this study adopts an integrative approach drawing on two complementary theories of transaction cost economics (TCE) and social capital to investigate how a firm creates synergy in overseas Chinese business networks. A multiple regression method was used to test hypotheses. The results indicate that repeat transactions and close ties with government offices and financial institutions contributed positively towards a firm's synergy creation while other variables such as trust, transaction uncertainty and information sharing did not show any significant relationship with synergy creation. Data from 108 Hong Kong-based Chinese manufacturing firms provide evidence that the integrative approach is rather effective in studying a firm's synergy creation in the context of interorganisational relationships.

To explore the preparedness of medical students towards advance directives and related end-of-life issues, and to examine background factors such as knowledge, attitudes, and experience concerning advance directives and related end-of-life issues.In 2007, 448 medical students in years 3 to 5 were surveyed at the Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. Their knowledge, attitudes, and experiences of advance directives and related end-of-life issues, and their self-perceived preparedness to discuss these matters with patients were evaluated.A total of 220 (49%) of the eligible students responded, of whom 79% supported the use of advance directives. Only 65 (30%) students were certain of what advance directives meant and 198 (90%) students felt that their knowledge of advance directives was inadequate. Also, 197 (90%) students felt unprepared about advance directives and end-of-life issues. Factors associated with positive attitude towards advance directives included religion and knowledge. No factors were found to be associated with self-perceived preparedness towards advance directives or end-of-life issues.Most of the medical students surveyed demonstrated a positive attitude towards advance directives and recognised the importance of advance directives. However, they felt that they were unprepared and lacking in knowledge and experience of advance directives and end-of-life issues. Wider range and more depth of education is needed to better equip medical students for future practice.

Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell-like and activated B-cell-like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1, and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B-cells. Cutoffs for each marker were obtained using receiver operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1, and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.Leukemia accepted article preview online, 22 March 2012; doi:10.1038/leu.2012.83.