Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study
Abstract
Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.
Article Details
Authors (55)
Andrew L. Feldman
1Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN
Surendra Dasari
Lisa M. Rimsza
3Department of Pathology and Laboratory Medicine, The University of Arizona College of Medicine and Science, Tucson, AZ
David W. Scott
5Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, Canada
Naoki Oishi
Guangzhen Hu
1Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN
Pedro Farinha
6BC Cancer, Vancouver, BC, Canada
Catalina Amador
7Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL
Elias Campo
Wing C. Chan
James R. Cook
10Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH
Jan Delabie
University Health Network, Toronto
Kai Fu
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, School of Materials Science and Engineering
Timothy C. Greiner
Laura K. Hilton
4Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
Giorgio Inghirami
Javeed Iqbal
Elaine S. Jaffe
11Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Ryan D. Morin
4Centre for Lymphoid Cancer, BC Cancer Research Institute, Vancouver, BC, Canada
Sarah L. Ondrejka
10Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH
German Ott
16Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Stefania Pittaluga
Philipp W. Raess
17Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR
Andreas Rosenwald
Kerry J. Savage
6BC Cancer, Vancouver, BC, Canada
Graham W. Slack
6BC Cancer, Vancouver, BC, Canada
Susan L. Slager
2Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN
Joo Y. Song
George W. Wright
19Biometric Research Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Bethesda, MD
Hao-Wei Wang
Yu Zeng
Tadashi Yoshino
21Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Xiaojun Wu
Ryan A. Wilcox
23Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, MI
Xueju Wang
Min Shi
East China University of Science and Technology , , 130 Meilong Road , ,
Akira Satou
Anamarija M. Perry
26Department of Pathology, University of Michigan, Ann Arbor, MI
Roberto N. Miranda
27Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
L. Jeffrey Medeiros
27Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
Matthew J. Maurer
2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
Eric Mou
24Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA
Young-Hyeh Ko
29Department of Pathology, Guro Hospital, Korea University College of Medicine, Seoul, Korea
Kennosuke Karube
30Department of Pathology and Laboratory Medicine, Nagoya University, Nagoya, Japan
Brad S. Kahl
30Division of Oncology, Washington University School of Medicine, St. Louis, MO
Liuyan Jiang
32Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Jacksonville, FL
David L. Jaye
33Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
Alejandro A. Gru
34Dermatopathology Section, Columbia University Irving Medical Center/New York–Presbyterian, New York, NY
Laurence de Leval
Weina Chen
Department of Pathology, University of Texas Southwestern Medical Center
Jennifer R. Chapman
7Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL
James R. Cerhan
Carlos Barrionuevo
37Departamento de Patología, Instituto Nacional de Enfermedades Neoplásicas, and Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Peru
Stephen M. Ansell
3Department of Hematology/Oncology, Mayo School of Graduate Medicine, Mayo Clinic, Rochester, MN
Ahmed A. Aljudi
39Department of Pathology, Children’s Healthcare of Atlanta, Atlanta, GA