Gastroenterology

Gastroenterology

Volume 132, Issue 5, May 2007, Pages 1902-1911
Gastroenterology

Basic–alimentary tract
Whole-Genome Analysis and HLA Genotyping of Enteropathy-Type T-Cell Lymphoma Reveals 2 Distinct Lymphoma Subtypes

https://doi.org/10.1053/j.gastro.2007.03.036Get rights and content

Background & Aims: Enteropathy-type T-cell lymphoma (ETL) is an aggressive extranodal T-cell non-Hodgkin lymphoma assumed to arise in the setting of celiac disease. Methods: To precisely define the genetic alterations underlying the pathogenesis of ETL, 30 ETL samples were profiled for genetic copy number alterations using high-resolution whole-genome tiling path array comparative genomic hybridization. To investigate the potential association of genetic alterations in ETL with celiac disease, HLA-DQB1 genotyping was performed. Results: By array comparative genomic hybridization, 13 novel recurrent minimal regions of chromosomal alteration were identified on multiple chromosome arms. ETL is characterized by frequent complex gains of 9q31.3-qter (70% of cases), or by an almost mutually exclusive 2.5-megabase loss of 16q12.1 (23% of cases). Two distinct groups of ETL could be delineated morphologically and genetically: type 1 ETL is characterized by nonmonomorphic cytomorphology, CD56 negativity, and chromosomal gains of 1q and 5q. Type 1 ETL also appears to be linked pathogenetically to celiac disease, sharing genetic alterations and HLA-DQB1 genotype patterns with (refractory) celiac disease. Type 2 ETL shows monomorphic small- to medium-sized tumor cell morphology, frequently shows CD56 expression, MYC oncogene locus gain, and rare gains of chromosomes 1q and 5q. In contrast to type 1 ETL, type 2 ETL shows a HLA-DQB1 genotype pattern more resembling that of the normal Caucasian population. Conclusions: Contrary to current clinical classification, ETL comprises 2 morphologically, clinically, and genetically distinct lymphoma entities. In addition, type 2 ETL may not be associated with celiac disease.

Section snippets

Morphologic and Clinical Features of ETL Cases

Thirty cases of ETL were selected from the archive of the Lymph Node Reference Center at the Department of Pathology, University of Würzburg, Germany, and from the archive of the Department of Pathology, University of Vienna, Austria. All cases had been classified as ETL based on the criteria defined by the World Health Organization classification of tumors of hematopoietic and lymphoid tissues.10 All cases were reviewed before inclusion in the study. Before the array CGH study, 18 of the 30

Immunohistochemical Analysis of ETL Cases

The immunophenotypical features of the cases are summarized in Table 1. Briefly, the majority of ETL cases (26 of 30) were CD3+/CD4. Of the remaining 4 cases, 3 were CD3/CD4 and 1 was CD3/CD4+. Seventeen ETL cases were CD8+, of which 10 were of monomorphic small- to medium-sized tumor cell morphology. Anaplastic large-cell morphology correlated with CD30 positivity (P = .037) and CD8 negativity (P = .026). Fifteen ETL cases were CD56+, 13 of which were monomorphic, whereas the remaining 2

Discussion

To determine genetic alterations associated with ETL morphology, immunophenotype, and celiac disease–associated HLA genotypes, we studied 30 ETL cases by tiling-path whole-genome array CGH, a molecular technique that allows high-resolution screening of genetic alterations with a resolution of an order of magnitude higher than previous chromosomal CGH and microsatellite analyses.17 Relatively little work has been published on T-cell lymphomas using these new high-resolution techniques. One study

References (30)

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    EATL most commonly presents with abdominal pain, malabsorption, diarrhea, weight loss and extra-intestinal spread is rare. TRB or TRG genes are clonally rearranged in almost all cases and most EATLs either show gains of the 9q34 region or deletions of 16q12.1 and HLA-DQ2 haplotype.5 MEITL is an intestinal T-cell lymphoma derived, as like as EATL, from intraepithelial lymphocytes.

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Supported by funds from Genome Canada/British Columbia and the Canadian Institute of Health Research; and by the Interdisziplinäres Zentrum für Klinische Forschung, Würzburg, Germany; and by scholarships from the National Sciences and Engineering Council of Canada and the Michael Smith Foundation for Health Research.

1

R.J.D. and A.Z. contributed equally to this study.

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