Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data

Gong, Qiang; Wang, Chao; Zhang, Weiwei; Iqbal, Javeed; Hu, Yang; Greiner, Timothy C.; Cornish, Adam; Kim, Jo Heon; Rabadán, Raúl; Abate, Francesco; Wang, Xin; Inghirami, Giorgio; McKeithan, Timothy W.; Chan, Wing C.

doi:10.1038/s41598-017-11310-0

Cited by 30 publications

(32 citation statements)

References 46 publications

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“…41 Consistent with our results, a similar phenomenon was reported by Gong et al in the case of angioimmunoblastic T-cell lymphoma. 42 Also, considering that mutations involved in activating TCR signaling have been observed in ATL, 31 these mutations may allow for signaling for survival and proliferation in the absence of functional TCRs in such ATL cases. The mechanism responsible for abnormalities in TCR expression is of interest and needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

2019

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The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1−infected individuals—asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes—and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCRα and TCRβ genes in the dominant clone differed among the samples. ACs, CD4 - positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.

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Section: Discussionmentioning

confidence: 99%

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

2019

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“…The method is especially useful for identification of TCRα locus rearrangements that do not amplify reliably with multiplex PCR due to large number of V and J genes. To date, all data on TCRα were gathered with RNA sequencing 18,19 and very little is known about the diversity of TCRα at the DNA level.…”

Section: Discussionmentioning

confidence: 99%

“…Other groups that performed TCR sequencing in CTCL also found evidence of oligoclonality 20 . Recently, Ruggiero et al 18 using ligation-anchored PCR mRNA amplification and sequencing of TCRα and TCRβ in Sézary syndrome found oligoclonal, rather than monoclonal pattern in 4/10 patients and polyclonal TCR repertoire was reported in subgroups of patients with PTCL-NOS or AITL 19 . Supportive evidence comes also from the studies showing multiple TCRβ transcripts in CTCL with the copy number aberration of chromosome 7 containing TCRβ.…”

Section: Discussionmentioning

confidence: 99%

Clonotypic Heterogeneity In Cutaneous T-Cell Lymphoma Revealed By Comprehensive Whole Exome/Transcriptome Sequencing

Iyer

Patterson

Salopek

et al. 2018

Preprint

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Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin resident memory T-cell. T-cell receptor (TCR) clonality (i.e. identical sequences of rearranged TCRα, β and γ), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor infiltrating, reactive lymphocytes, which contribute to the TCR clonotypic repertoire of MF. Here we have successfully adopted the technique of targeted whole exome and whole transcriptome sequencing (WES/WTS) to identify the repertoire of rearranged TCR genes in tumor enriched samples from patients with MF. Although most of the investigated biopsies of MF had the expected monoclonal rearrangements of TCRγ of the frequency corresponding to the frequency of tumor cells, in half of the samples we detected multiple (up to seven) TCRα and -β clonotypes by WES and WTS. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature, memory T-cells but rather at the level of T-lymphocyte progenitor after TCRγ rearrangement but before TCRβ or TCRα rearrangements. The WES/WTS method is potentially applicable to other types of T-cell lymphomas and enables comprehensive characterization of the TCR repertoire and mutational landscape in these malignancies. We would like to thank Dr. Weiwei Wang for his input in the study design. We would also like to acknowledge Mrs. Rachel Doucet and the nursing staff of Edmonton Kaye clinic for their help in sample collection.

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“…Reactivated transposable elements and retrotransposed mRNAs are involved in tumorigenesis [61] and Alzheimer’s disease [62]. Rearranged T-cell receptor transcripts are used to monitor T-cell clonal expansion in tumors [63]. Both A-to-I RNA editing events and M6A base modifications contribute to cancer progression [37].…”

Section: Ignore Non-reference Transcripts At Your Own Risksmentioning

confidence: 99%

Bridging the gap between reference and real transcriptomes

Morillon

Gautheret

2019

Genome Biol

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Genetic, transcriptional, and post-transcriptional variations shape the transcriptome of individual cells, rendering establishing an exhaustive set of reference RNAs a complicated matter. Current reference transcriptomes, which are based on carefully curated transcripts, are lagging behind the extensive RNA variation revealed by massively parallel sequencing. Much may be missed by ignoring this unreferenced RNA diversity. There is plentiful evidence for non-reference transcripts with important phenotypic effects. Although reference transcriptomes are inestimable for gene expression analysis, they may turn limiting in important medical applications. We discuss computational strategies for retrieving hidden transcript diversity. Electronic supplementary material The online version of this article (10.1186/s13059-019-1710-7) contains supplementary material, which is available to authorized users.

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Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data

Cited by 30 publications

References 46 publications

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

Clonotypic Heterogeneity In Cutaneous T-Cell Lymphoma Revealed By Comprehensive Whole Exome/Transcriptome Sequencing

Bridging the gap between reference and real transcriptomes

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