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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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/66395 |
| _version_ | 1811199881114550272 |
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| author | Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam |
| author_facet | Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam |
| author_sort | Shuhua Cheng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:55:02Z |
| format | Article |
| id | doaj.art-a27d55bdfc5a40f69b987bae0c445bcb |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:55:02Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a27d55bdfc5a40f69b987bae0c445bcb2022-12-22T03:52:49ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.66395Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smokingShuhua Cheng0Wei Zhang1Giorgio Inghirami2Wayne Tam3https://orcid.org/0000-0003-4283-0005Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United StatesGenomics Resources Core Facility, Weill Cornell Medicine, New York, United StatesDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United StatesDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United StatesBackground: 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.https://elifesciences.org/articles/66395angioimmunoblastic t cell lymphomaclonal hematopoiesisconcurrent hematologic neoplasmmutated hematopoietic precursorsmokingbiomarker |
| spellingShingle | Shuhua Cheng Wei Zhang Giorgio Inghirami Wayne Tam Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking eLife angioimmunoblastic t cell lymphoma clonal hematopoiesis concurrent hematologic neoplasm mutated hematopoietic precursor smoking biomarker |
| title | 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_short | 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 |
| topic | angioimmunoblastic t cell lymphoma clonal hematopoiesis concurrent hematologic neoplasm mutated hematopoietic precursor smoking biomarker |
| url | https://elifesciences.org/articles/66395 |
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