Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma.

Anaplastic large-cell lymphomas (ALCLs) are a group of clinically and biologically heterogeneous diseases including the ALK(+) and ALK(-) systemic forms. Whereas ALK(+) ALCLs are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK(-) ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) remains controversial. In the present study, we undertook a transcriptional profiling meta-analysis of 309 cases, including ALCL and other primary T-NHL samples. Pathway discovery and prediction analyses defined a minimum set of genes capable of recognizing ALK(-) ALCL. Application of quantitative RT-PCR in independent datasets from cryopreserved and formalin-fixed paraffin-embedded samples validated a 3-gene model (TNFRSF8, BATF3, and TMOD1) able to successfully separate ALK(-) ALCL from peripheral T-cell lymphoma not otherwise specified, with overall accuracy near 97%. In conclusion, our data justify the possibility of translating quantitative RT-PCR protocols to routine clinical settings as a new approach to objectively dissect T-NHL and to select more appropriate therapeutic protocols.

[1]  A. Rosenwald,et al.  Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. , 2005, Human pathology.

[2]  A. Kwiecińska,et al.  High resolution SNP array genomic profiling of peripheral T cell lymphomas, not otherwise specified, identifies a subgroup with chromosomal aberrations affecting the REL locus , 2010, British journal of haematology.

[3]  S. Pileri,et al.  Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. , 2007, Cancer research.

[4]  M. Tallman,et al.  T-cell non-Hodgkin lymphoma. , 2006, Blood.

[5]  P. Gaulard,et al.  Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. , 2007, Blood.

[6]  Enzo Medico,et al.  Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  R. Gascoyne,et al.  Genomic profiling reveals different genetic aberrations in systemic ALK‐positive and ALK‐negative anaplastic large cell lymphomas , 2008, British journal of haematology.

[8]  S. Bicciato,et al.  Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  C. Croce,et al.  miR-155: On the Crosstalk Between Inflammation and Cancer , 2009, International reviews of immunology.

[10]  J. Itami,et al.  Hodgkin-like anaplastic large cell lymphoma (previously designated in the REAL classification) has same immunophenotypic features to classical Hodgkin lymphoma , 2007, Leukemia & lymphoma.

[11]  Elias Campo,et al.  The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. , 2011, Blood.

[12]  M. Desouki,et al.  PAX-5: A Valuable Immunohistochemical Marker in the Differential Diagnosis of Lymphoid Neoplasms , 2010, Clinical Medicine & Research.

[13]  M Paulli,et al.  Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma , 2009, Leukemia.

[14]  References , 1971 .

[15]  K. Lennert,et al.  The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. , 1985, Blood.

[16]  C. Corless.  Personalized Cancer Diagnostics , 2011, Science.

[17]  Stefano A Pileri,et al.  Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. , 2007, The Journal of clinical investigation.

[18]  G. Inghirami,et al.  The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination , 2008, Nature Medicine.

[19]  S. Pileri,et al.  Expression of platelet-derived growth factor receptor alpha in peripheral T-cell lymphoma not otherwise specified. , 2005, The Lancet. Oncology.

[20]  David I. Smith,et al.  Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. , 2011, Blood.

[21]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[22]  J. Benítez,et al.  Expression Profiling of T-Cell Lymphomas Differentiates Peripheral and Lymphoblastic Lymphomas and Defines Survival Related Genes , 2004, Clinical Cancer Research.

[23]  J. Wisell.  Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies , 2012 .

[24]  Christian Gisselbrecht,et al.  The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. , 2007, Blood.

[25]  A. Rosenwald,et al.  Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling. , 2004, Blood.

[26]  W. Chan,et al.  Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. , 2010, Blood.

[27]  M. Djokic.  ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project , 2009 .

[28]  G. Ossenkoppele,et al.  ALK‐negative anaplastic large‐cell lymphoma demonstrates similar poor prognosis to peripheral T‐cell lymphoma, unspecified , 2003, Histopathology.

[29]  G. Inghirami,et al.  Anaplastic large cell lymphoma: one or more entities among T‐cell lymphoma? , 2009, Hematological oncology.

[30]  J. Vose,et al.  Peripheral T-cell lymphoma. , 2011, Blood.

[31]  D. Weisenburger,et al.  International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  R. Greil,et al.  Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK− anaplastic large-cell lymphoma , 2010, Proceedings of the National Academy of Sciences.

[33]  P. Gaulard,et al.  Prognostic Factors and Long Term Outcome of 138 Adults with Systemic Anaplastic Large-Cell Lymphoma: a Retrospective Study by the Groupe d'Etude Des Lymphomes De l'Adulte (GELA) , 2010 .

[34]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[35]  S. Pileri,et al.  Expression of platelet-derived growth factor receptor α in peripheral T-cell lymphoma not otherwise specified , 2005 .