T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes

Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore

Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore

⁴

Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore 138632, Singapore

⁵

Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore

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Viva-NUS Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

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VIVA—University Children’s Cancer Centre, Khoo Teck Puat–National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore 119074, Singapore

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Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore

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Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore

¹⁰

Department of Pathology, Chi-Mei Medical Center, Tainan 71004, Taiwan

¹¹

Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan

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Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 464-0021, Japan

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Department of Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan

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Department of Pathology, Tan Tock Seng Hospital, Singapore 308433, Singapore

¹⁵

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

¹⁶

Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

¹⁷

Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore

¹⁸

Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore

¹⁹

Department of Hematology-Oncology, National University Cancer Institute Singapore, National University Hospital, National University Health System, Singapore 119074, Singapore

²⁰

Tumor Immunology Unit, University of Palermo School of Medicine, 90134 Palermo, Italy

²¹

Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Singapore 138632, Singapore

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Cancers 2021, 13(2), 340; https://doi.org/10.3390/cancers13020340

Received: 25 December 2020 / Accepted: 11 January 2021 / Published: 19 January 2021

(This article belongs to the Collection Innovations in Cancer Diagnostic Evaluation and Biomarker Detection)

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T-cells defend the human body from pathogenic invasion via specific recognition by T-cell receptors (TCRs). The TCR genes undergo recombination (rearrangement) in a myriad of possible ways to generate different TCRs that can recognize a wide diversity of foreign antigens. However, in patients with T-cell lymphoma (TCL), a particular T-cell becomes malignant and proliferates, resulting in a population of genetically identical cells with same TCR rearrangement pattern. To help diagnose patients with TCL, a polymerase chain reaction (PCR)-based assay is currently used to determine if neoplastic cells in patient samples are of T-cell origin and bear identical (monoclonal) TCR rearrangement pattern. Herein, we report the application of a novel segmentation and copy number computation algorithm to accurately identify different TCR rearrangement patterns using data from the whole genome sequencing of patient materials. Our approach may improve the diagnostic accuracy of TCLs and can be similarly applied to the diagnosis of B-cell lymphomas.

Abstract

T-cell lymphomas arise from a single neoplastic clone and exhibit identical patterns of deletions in T-cell receptor (TCR) genes. Whole genome sequencing (WGS) data represent a treasure trove of information for the development of novel clinical applications. However, the use of WGS to identify clonal T-cell proliferations has not been systematically studied. In this study, based on WGS data, we identified monoclonal rearrangements (MRs) of T-cell receptors (TCR) genes using a novel segmentation algorithm and copy number computation. We evaluated the feasibility of this technique as a marker of T-cell clonality using T-cell lymphomas (TCL, n = 44) and extranodal NK/T-cell lymphomas (ENKTLs, n = 20), and identified 98% of TCLs with one or more TCR gene MRs, against 91% detected using PCR. TCR MRs were absent in all ENKTLs and NK cell lines. Sensitivity-wise, this platform is sufficiently competent, with MRs detected in the majority of samples with tumor content under 25% and it can also distinguish monoallelic from biallelic MRs. Understanding the copy number landscape of TCR using WGS data may engender new diagnostic applications in hematolymphoid pathology, which can be readily adapted to the analysis of B-cell receptor loci for B-cell clonality determination. View Full-Text

Keywords: whole genome sequencing; T-cell receptor; clonality; copy number variation analysis; T-cell lymphoma

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MDPI and ACS Style

Oon, M.L.; Lim, J.Q.; Lee, B.; Leong, S.M.; Soon, G.S.-T.; Wong, Z.W.; Lim, E.H.; Li, Z.; Yeoh, A.E.J.; Chen, S.; Ban, K.H.K.; Chung, T.-H.; Tan, S.-Y.; Chuang, S.-S.; Kato, S.; Nakamura, S.; Takahashi, E.; Ho, Y.-H.; Khoury, J.D.; Au-Yeung, R.K.H.; Cheng, C.-L.; Lim, S.-T.; Chng, W.-J.; Tripodo, C.; Rotzschke, O.; Ong, C.K.; Ng, S.-B. T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes. Cancers 2021, 13, 340. https://doi.org/10.3390/cancers13020340

AMA Style

Oon ML, Lim JQ, Lee B, Leong SM, Soon GS-T, Wong ZW, Lim EH, Li Z, Yeoh AEJ, Chen S, Ban KHK, Chung T-H, Tan S-Y, Chuang S-S, Kato S, Nakamura S, Takahashi E, Ho Y-H, Khoury JD, Au-Yeung RKH, Cheng C-L, Lim S-T, Chng W-J, Tripodo C, Rotzschke O, Ong CK, Ng S-B. T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes. Cancers. 2021; 13(2):340. https://doi.org/10.3390/cancers13020340

Chicago/Turabian Style

Oon, Ming L., Jing Q. Lim, Bernett Lee, Sai M. Leong, Gwyneth S.-T. Soon, Zi W. Wong, Evelyn H. Lim, Zhenhua Li, Allen E.J. Yeoh, Shangying Chen, Kenneth H.K. Ban, Tae-Hoon Chung, Soo-Yong Tan, Shih-Sung Chuang, Seiichi Kato, Shigeo Nakamura, Emiko Takahashi, Yong-Howe Ho, Joseph D. Khoury, Rex K.H. Au-Yeung, Chee-Leong Cheng, Soon-Thye Lim, Wee-Joo Chng, Claudio Tripodo, Olaf Rotzschke, Choon K. Ong, and Siok-Bian Ng. 2021. "T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes" Cancers 13, no. 2: 340. https://doi.org/10.3390/cancers13020340

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T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes

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