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

Abstract
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Abstract

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), remains 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 2 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, PPV=88.9%, NPV=92.1%).

Conclusion:

We provided genetic evidence that AITL/PTCL-NOS, CH, 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.

Data availability

All relevant data are included in this manuscript and the supplementary files.

The following previously published data sets were used

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Article and author information

Author details

Shuhua Cheng

Weill Cornell Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Wei Zhang

Weill Cornell Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Giorgio Inghirami

Weill Cornell Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Wayne Tam

Weill Cornell Medicine, New York, United States

For correspondence
wtam@med.cornell.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4283-0005

Funding

National Cancer Institute (R01 CA194547)

Wayne Tam

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was conducted in accordance with the Declaration of Helsinki regulations of the protocols approved by the Institutional Review Board of Weill Cornell Medicine, New York, USA. Written consent for use of the samples for research was obtained from patients or their guardians.(#0107004999)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.