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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 575-575
Author(s):  
Sarah Lynn Ondrejka ◽  
Andrea B. Moffitt ◽  
Eric Tse ◽  
Eric D. Hsi ◽  
John R. Goodlad ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Expression Patterns ◽  
T Cell Lymphoma ◽  
Sequencing Data ◽  
Whole Exome

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.

scholarly journals Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma

2019 ◽  
Vol 3 (4) ◽  
pp. 588-595 ◽  
Author(s):  
Chantana Polprasert ◽  
Yasuhide Takeuchi ◽  
Nobuyuki Kakiuchi ◽  
Kenichi Yoshida ◽  
Thamathorn Assanasen ◽  
...  
Keyword(s):  
T Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Germline Mutations ◽  
T Cell Lymphoma ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Whole Exome ◽  
History Of ◽  
Underlying Diseases

Abstract Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable–like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.

scholarly journals Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 148-155 ◽  
Author(s):  
Jan Delabie ◽  
Harald Holte ◽  
Julie M. Vose ◽  
Fred Ullrich ◽  
Elaine S. Jaffe ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
T Cell Lymphoma ◽  
World Health ◽  
Peripheral T Cell Lymphoma

Abstract Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)–cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.

scholarly journals Primary Pulmonary T-Cell Lymphoma in a Human T-Lymphotropic Virus Type-1 Carrier Showing Atypical Shadow

2010 ◽  
Vol 5 (4) ◽  
pp. 558-559 ◽  
Author(s):  
Shojiro Minomo ◽  
Takayuki Takimoto ◽  
Osamu Morimura ◽  
Akane Watanabe ◽  
Yasuhiro Nagate ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Lymphotropic Virus

scholarly journals T-Cell Lymphoma in a Patient with Neurofibromatosis Type 1 and AIDS

2017 ◽  
Vol 10 (1) ◽  
pp. 161-168
Author(s):  
Izana Junqueira de Castro ◽  
Esther Botelho Soares da Silva ◽  
Talita Rezende dos Santos ◽  
Amanda Barroso de Freitas ◽  
Inara Junqueira de Castro ◽  
...  
Keyword(s):  
T Cell ◽  
Neurofibromatosis Type 1 ◽  
Cell Lymphoma ◽  
Neurofibromatosis Type ◽  
T Cell Lymphoma ◽  
Malignant Neoplasms ◽  
Non Hodgkin Lymphoma ◽  
Dominant Disease ◽  
Chemotherapeutic Treatment

Neurofibromatosis type 1 (NF1) and AIDS are risk factors for the development of malignant neoplasms, including hematological malignancies, such as non-Hodgkin lymphoma. NF1 is an autosomal dominant disease that primarily manifests as café-au-lait spots, dermal neurofibromas, axillary and/or inguinal ephelides or freckles, plexiform neurofibromas, Lisch nodules, and bone deformities. In this report, we present a 38-year-old female patient with NF1 from childhood and AIDS who developed peripheral T-cell lymphoma with good response to chemotherapeutic treatment.

scholarly journals Outcomes of GDPT (gemcitabine, cisplatin, prednisone, thalidomide) versus CHOP in newly diagnosed peripheral T-cell lymphoma patients

2020 ◽  
Vol 12 ◽  
pp. 175883592092382 ◽  
Author(s):  
Yuanyuan Sun ◽  
Ling Li ◽  
Xin Li ◽  
Lei Zhang ◽  
Xinhua Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
The Other ◽  
Newly Diagnosed ◽  
Peripheral T Cell Lymphoma ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Significant Difference ◽  
Gene Expression Levels

Aim: To compare the outcomes of GDPT [gemcitabine (G), cisplatin (D), prednisone (P), thalidomide (T)] versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in treating newly diagnosed PTCL (peripheral T-cell lymphoma). Methods: An open-label prospective clinical trial with 153 newly diagnosed PTCL patients conducted between January 2010 and December 2018 was designed. Patients were randomly assigned to the GDPT (77 cases) and CHOP (76 cases) groups. Patients in each group were further divided into four subgroups: PTCL, not otherwise specified (PTCL-NOS); anaplastic large cell lymphoma (ALCL), angioimmunoblastic T cell lymphoma (AITL), and other types subgroup, in accordance with pathological patterns. Based on expression of RRM1, TOP2A, TUBB3, and ERCC1, patients were divided into groups with high and low gene expression levels. Clinical characteristics, side effects, efficacy, progression-free survival (PFS), and overall survival (OS) were compared. Results: There were no significant differences in the basic clinical features or side effects between the GDPT and CHOP groups. The overall response rate (ORR) of the GDPT group was better than that of the CHOP group (66.3% versus 50.0%, p = 0.042), as was the complete remission (CR) rate (42.9% versus 27.6%, p = 0.049). Patients in the GDPT group had a longer PFS and OS than the CHOP group. The 4-year PFS and OS rates in the GDPT group were both superior to those in the CHOP group (63.6% versus 53.0% for PFS, p = 0.035; 66.8% versus 53.6% for OS, p = 0.039). In the GDPT group, the difference in CR between the four subgroups was statistically significant ( p = 0.046). In the CHOP group, differences in both CR and ORR among the four subgroups were statistically significant ( p < 0.001 and p = 0.005, respectively). There were also statistically significant differences in CR between patients treated with CHOP and GDPT in the PTCL-NOS subgroup, AITL subgroup, and the other types subgroup ( p = 0.015; p = 0.003; p = 0.005, respectively). The data also showed a significant difference in OS among the four subgroups within the GDPT group ( p = 0.001). The OS of AITL was shorter than that of the other three subgroups. Four subgroups of CHOP showed a significant difference in PFS ( p = 0.019). There was no statistical association between responses and the gene expression levels of RRM1, ERCC1, TUBB3, and TOP2A. Conclusion: The GDPT group had better response rates and prolonged patient PFS and OS. As a promising new regimen, GDPT is expected to become the first-line therapy for PTCL. New agents should be applied to patients who do not achieve good responses with previous treatment, such as those diagnosed with angioimmunoblastic T cell lymphoma. Trial registration: This open randomized prospective clinical trial was registered at ClinicalTrials.gov (NCT01664975).

scholarly journals Neoantigens Derived from Recurrently Mutated Genes as Potential Immunotherapy Targets for Gastric Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Zhou ◽  
Wenyi Zhao ◽  
Jingcheng Wu ◽  
Jun Lu ◽  
Yongfeng Ding ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Sequencing Data ◽  
Driver Genes ◽  
Cell Immunotherapy ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Gastric Cancer Patients

Neoantigens are optimal tumor-specific targets for T-cell based immunotherapy, especially for patients with “undruggable” mutated driver genes. T-cell immunotherapy can be a “universal” treatment for HLA genotype patients sharing same oncogenic mutations. To identify potential neoantigens for therapy in gastric cancer, 32 gastric cancer patients were enrolled in our study. Whole exome sequencing data from these patients was processed by TSNAD software to detect cancer somatic mutations and predict neoantigens. The somatic mutations between different patients suggested a high interpatient heterogeneity. C>A and C>T substitutions are common, suggesting an active nucleotide excision repair. The number of predicted neoantigens was significantly higher in patients at stage T1a compared to in patients at T2 or T4b. Six genes (PIK3CA, FAT4, BRCA2, GNAQ, LRP1B, and PREX2) were found as recurrently mutated driver genes in our study. Combining with highly frequent HLA alleles, several neoantigens derived from six recurrently mutated genes were considered as potential targets for further immunotherapy.

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

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4952-4963 ◽  
Author(s):  
Laurence de Leval ◽  
David S. Rickman ◽  
Caroline Thielen ◽  
Aurélien de Reynies ◽  
Yen-Lin Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Molecular Profile ◽  
Peripheral T Cell Lymphoma ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Tfh Cells ◽  
Follicular Helper

Abstract The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell– and follicular dendritic cell–related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (TFH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published TFH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several TFH genes was validated by immunohistochemistry in AITLs. A few cases with molecular TFH-like features were identified among CD30− PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30− PTCLs-u may derive from or be related to AITL.

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