Whole Exome Sequencing of Type 1 and Type 2 Enteropathy-Associated T Cell Lymphoma Reveals Genetic Basis of Eatl Oncogenesis

Abstract

Introduction Enteropathy-associated T cell lymphoma (EATL) is an intestinal tumor of the intraepithelial T lymphocytes, with a median survival time of less than 1 year. It is a rare disease in general and has two main subtypes described. Type 1 EATL is a complication in patients with celiac disease, a chronic gluten-sensitive enteropathy. Type 2 EATL, characterized by smaller monomorphic lymphocytes, typically occurs sporadically in patients without celiac disease. Very little is known about the genetic mutations and gene expression signatures that define this disease, or the extent to which the two types of EATL are genetically distinct. It has been suggested that the two types of EATLs should be reclassified as separate diseases in future WHO categories. Methods In this study, we performed whole exome sequencing to 100-fold depth of 41 EATL tumors including 23 type 1 cases and 18 type 2 cases. Both alpha-beta (65%) and gamma-delta (35%) T cell receptor rearrangements were seen among these cases. Paired normal DNA was sequenced in most (N=30) cases. We defined somatic mutations, copy number alterations, and HLA genotypes in these cases from sequencing data. Additionally, we generated RNA sequencing data on the same EATL tumors. Corresponding clinical and outcome data was collected on the same cohort. Results We found that both type 1 and type 2 EATLs had overlapping patterns of mutations and similar overall survival. The most commonly mutated genes were chromatin modifier genes (34%) including ATRX and ARID1B. We also identified recurrent somatic mutations in signal transduction genes, including JAK1 and BCL9L. TP53 mutations were also recurrent (12%). Copy number amplifications in 9q, 1q, and 8q occurred most frequently and were present in both subtypes. We further compared the mutational profiles to peripheral T cell lymphoma, angioimmunoblastic T cell lymphoma, cutaneous T cell lymphoma, natural killer/T cell lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma. These comparisons identify EATL as a genetically distinct disease with a very different pattern of mutations. RNAseq identified the gene expression patterns that are unique to EATL and also identified gene expression signatures that distinguish the two types of EATL. The DQ2 or DQ8 HLA genotype is present in the majority of type 1 cases (73%) while occurring infrequently in type 2 cases (27%). Conclusions Our study defines the genetic landscape of enteropathy associated T cell lymphoma and highlights the genetic and clinical overlap between the two types. While the two types have differences in mutations and gene expression patterns, they have more in common with each other compared to other lymphoma types. Our data may inform future decisions regarding the potential separation of the two EATL types as distinct entities. Disclosures No relevant conflicts of interest to declare.

Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders

“…The mutational landscape is quite similar to those seen in EATL, although mutations of KRAS and SETD2 are more common in MEITL [217]. Of higher frequencies are mutations of SETD2 [217,247,249,250], TP53 [215,217,223,250], KRAS [217,250], members of the JAK-STAT [217,247,[249][250][251] and G-protein-coupled receptor signalling pathways [247,249]. In keeping with this, miRNA profiling also shows over-representation of JAK-STAT, MAPK and PI3K-AKT pathways [252].…”

“…Cytogenetic alterations include gains of 9q31.3qter and losses at 16q12.1, as with EATL [219,243,247]. Alterations in EATL such as gains of 1q32.2-q41 and 5q34-q35.5 were reported by some authors [215,243,244] but not others [214,247]. Other alterations in MEITL include gains of 9q22.31, 4p15.1, 7q34, 8p11.23 and 12p13.31; loss at 7p14.1 [243]; and gains or translocations of C-MYC [225,248].…”

“…Finally, EATLs display clonal rearrangements of TCRG and TCRB genes. Cytogenetic alterations include gains of 9q31.3-qter, 1q, 5q34-q35.2 and losses of 16q12.1 [214,215]. Frequent mutations reported include members of the JAK-STAT pathway (JAK1, JAK3, STAT3, STAT5B, SOCS1), chromatin modifiers (SETD2, TET2, YLPM1), RASpathway (NRAS, KRAS), DNA damage and response (TP53, BCL11B), DAPK1, BBX, TERT, and PRDM1 [216,217].…”