Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking

Background: Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS...

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Autores principales:	Shuhua Cheng, Wei Zhang, Giorgio Inghirami, Wayne Tam
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	angioimmunoblastic t cell lymphoma clonal hematopoiesis concurrent hematologic neoplasm mutated hematopoietic precursor smoking biomarker Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a27d55bdfc5a40f69b987bae0c445bcb
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spelling	oai:doaj.org-article:a27d55bdfc5a40f69b987bae0c445bcb2021-11-15T06:43:36ZMutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking10.7554/eLife.663952050-084Xe66395https://doaj.org/article/a27d55bdfc5a40f69b987bae0c445bcb2021-09-01T00:00:00Zhttps://elifesciences.org/articles/66395https://doaj.org/toc/2050-084XBackground: Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking. Methods: We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and two with PTCL-NOS. Results: Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH-associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥15% of allele burden conferred higher risk for CHN (p=0.0006, hazard ratio = 14.01, positive predictive value = 88.9%, negative predictive value = 92.1%). Conclusions: We provided genetic evidence that AITL/PTCL-NOS, CH, and CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients. Funding: R01 grant (CA194547) from the National Cancer Institute to WT.Shuhua ChengWei ZhangGiorgio InghiramiWayne TameLife Sciences Publications Ltdarticleangioimmunoblastic t cell lymphomaclonal hematopoiesisconcurrent hematologic neoplasmmutated hematopoietic precursorsmokingbiomarkerMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	angioimmunoblastic t cell lymphoma clonal hematopoiesis concurrent hematologic neoplasm mutated hematopoietic precursor smoking biomarker Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	angioimmunoblastic t cell lymphoma clonal hematopoiesis concurrent hematologic neoplasm mutated hematopoietic precursor smoking biomarker Medicine R Science Q Biology (General) QH301-705.5 Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
description	Background: Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking. Methods: We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and two with PTCL-NOS. Results: Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH-associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥15% of allele burden conferred higher risk for CHN (p=0.0006, hazard ratio = 14.01, positive predictive value = 88.9%, negative predictive value = 92.1%). Conclusions: We provided genetic evidence that AITL/PTCL-NOS, CH, and CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients. Funding: R01 grant (CA194547) from the National Cancer Institute to WT.
format	article
author	Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam
author_facet	Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam
author_sort	Shuhua Cheng
title	Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
title_short	Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
title_full	Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
title_fullStr	Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
title_full_unstemmed	Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking
title_sort	mutation analysis links angioimmunoblastic t-cell lymphoma to clonal hematopoiesis and smoking
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/a27d55bdfc5a40f69b987bae0c445bcb
work_keys_str_mv	AT shuhuacheng mutationanalysislinksangioimmunoblastictcelllymphomatoclonalhematopoiesisandsmoking AT weizhang mutationanalysislinksangioimmunoblastictcelllymphomatoclonalhematopoiesisandsmoking AT giorgioinghirami mutationanalysislinksangioimmunoblastictcelllymphomatoclonalhematopoiesisandsmoking AT waynetam mutationanalysislinksangioimmunoblastictcelllymphomatoclonalhematopoiesisandsmoking
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Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking

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