Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis

Dobson, Rachel; Du, Peter Y; Rásó‐Barnett, Lívia; Yao, Wenqing; Chen, Zi; Casà, Calogero; EIDaly, Hesham; Farkas, Lóránt; Soilleux, Elizabeth; Wright, Penny; Grant, J. W.; Rodriguez‐Justo, Manuel; Follows, George; Rashed, Hala; Fabre, M; Baxter, E. Joanna; Vassiliou, George S.; Wotherspoon, Andrew; Attygalle, Ayoma; Liu, Hongxiang; Du, Ming‐Qing

doi:10.3324/haematol.2020.265991

Cited by 21 publications

(22 citation statements)

References 31 publications

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“…However, the occult nature of the TFH cell proliferation in both LN specimens and the predominant clonal CTC proliferation/lymphoma at relapse suggest that the TFH cell proliferation might represent a smouldering AITL, or an early manifestation of AITL. 20 The impact of TET2 and DNMT3A mutations on the survival and expansion of B cells and T cells is unclear. Individuals with clonal haematopoiesis do not usually show peripheral blood lymphocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…In case 2, the systemic dissemination of occult RHOA ‐G17V‐mutant TFH cells and their preferential distribution around HEVs surrounded by mild extrafollicular FDC hyperplasia in LNs would be compatible with AITL. However, the occult nature of the TFH cell proliferation in both LN specimens and the predominant clonal CTC proliferation/lymphoma at relapse suggest that the TFH cell proliferation might represent a smouldering AITL, or an early manifestation of AITL 20 …”

Section: Discussionmentioning

confidence: 99%

“…The RHOA ‐G17V mutation was additionally investigated by qPCR with a peptide nucleic acid clamp and a locked nucleic acid probe, 20 which is highly sensitive, and suitable for use with crude DNA extracts. The qPCR was carried out in triplicate using 2–7.5 μl of crude DNA or 25 ng of purified DNA, with denaturation at 95°C for 30 s, followed by 45 cycles at 95°C for 3 s, and 62°C for 30 s.…”

Section: Methodsmentioning

confidence: 99%

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Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis

et al. 2022

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AimsAngioimmunoblastic T‐cell lymphoma (AITL) is genetically characterized by TET2 and DNMT3A mutations occurring in haematopoietic progenitor cells, and late events (e.g. the RHOA‐G17V mutation) associated with malignant transformation. As TET2/DNMT3A‐mutated progenitor cells can differentiate into multilineage progenies and give rise to both AITL and myeloid neoplasms, they may also have the potential to lead to other metachronous/synchronous neoplasms. We report two cases showing parallel evolution of two distinct potentially neoplastic lymphoid proliferations from a common mutated haematopoietic progenitor cell population.Methods and resultsBoth cases presented with generalized lymphadenopathy. In case 1 (a 67‐year‐old female), an initial lymph node (LN) biopsy was dismissed as reactive, but a repeat biopsy showed a nodal marginal zone lymphoma (NMZL)‐like proliferation with an increase in the number of T‐follicular helper (TFH) cells. Immunohistochemistry, and clonality and mutational analyses by targeted sequencing of both whole tissue sections and microdissected NMZL‐like lesions, demonstrated a clonal B‐cell proliferation that harboured the BRAF‐G469R mutation and shared TET2 and DNMT3A mutations with an underlying RHOA‐G17V‐mutant TFH proliferation. Review of the original LN biopsy showed histological and immunophenotypic features of AITL. In case 2 (a 66‐year‐old male), cytotoxic T‐cell lymphoma with an increase in the number of Epstein–Barr virus‐positive large B cells was diagnosed on initial biopsy. On review together with the relapsed biopsy, we identified an additional occult neoplastic TFH proliferation/smouldering AITL. Both T‐cell proliferations shared TET2 and DNMT3A mutations while RHOA‐G17V was confined to the smouldering AITL.ConclusionsIn addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis

et al. 2022

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“…Similarly, a recent study focusing on screening for the RHOA (G17V) mutation has demonstrated the relevance of mutation detection for the early diagnosis of PTCL with T-follicular helper (TFH) phenotype in specimens that showed no evidence of lymphoma after combined histological and clonality analyses. 9 Regarding our t-NGS approach, the pathogenicity of the mutations detected in samples with a negative PCR-based clonality might be questionable and raises the issue of clonal hematopoiesis (CH). Some of the genes included in our lymphoma panel have been shown to be related to CH (DNMT3A, EZH2, JAK2, TET2, TP53).…”

Section: Resultsmentioning

confidence: 99%

Molecular diagnosis of T-cell lymphoma: a correlative study of PCR-based T-cell clonality assessment and targeted NGS

et al. 2021

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Immunomorphological diagnosis of T-cell lymphomas (TCL) may be challenging, especially on needle biopsies. Multiplex polymerase chain reaction (PCR) assays to assess T-cell receptor (TCR) gene rearrangements are now widely used to detect T-cell clones and provide diagnostic support. However, PCR assays only detect 80% of TCL, and clonal lymphocyte populations may also appear in non-neoplastic conditions. More recently, targeted next-generation sequencing (t-NGS) technologies have been deployed to improve lymphoma classification. To the best of our knowledge, the comparison of these techniques' performance in TCL diagnosis has not been reported yet. In this study, 82 TCL samples and 25 non-neoplastic T-cell infiltrates were divided into two cohorts (test and validation) and analyzed with both multiplex PCR and t-NGS to investigate TCR gene rearrangements and somatic mutations, respectively. The detection of mutations appeared to be more specific (100.0%) than T-cell clonality assessment (41.7% to 45.5%), whereas no differences were observed in terms of sensitivity (95.1% to 97.4%). Furthermore, t-NGS provided a reliable basis for TCL diagnosis in samples with partially degraded DNA that was impossible to assess with PCR. Finally, although multiplex PCR assays appeared to be less specific than t-NGS, both techniques remain complementary, as PCR recovered some t-NGS negative cases.

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“…Occasionally, a negative result is observed: this can occur in cases of poor fixation or early neoplastic involvement, which turns out to be below the threshold of sensitivity of a conventional Sanger approach. Under the latter circumstances, a next-generation sequencing technique for TCR or recurrently mutated genes (see below) may provide evidence of the neoplastic nature of the process [ 24 ].…”

Section: Molecular Characteristicsmentioning

confidence: 99%

Peripheral T-Cell Lymphoma, Not Otherwise Specified: Clinical Manifestations, Diagnosis, and Future Treatment

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Tabanelli

Fiori

et al. 2021

Cancers

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Peripheral T-cell lymphoma, not otherwise specified (PTCL_NOS) corresponds to about one fourth of mature T-cell tumors, which overall represent 10–12% of all lymphoid malignancies. This category comprises all T-cell neoplasms, which do not correspond to any of the distinct entities listed in the WHO (World Health Organization) Classification of Tumours of Haematopoietic and Lymphoid Tissues. In spite of the extreme variability of morphologic features and phenotypic profiles, gene expression profiling (GEP) studies have shown a signature that is distinct from that of all remaining PTCLs. GEP has also allowed the identification of subtypes provided with prognostic relevance. Conversely to GEP, next-generation sequencing (NGS) has so far been applied to a limited number of cases, providing some hints to better understand the pathobiology of PTCL_NOS. Although several pieces of information have emerged from pathological studies, PTCL_NOS still remains a tumor with a dismal prognosis. The usage of CHOEP (cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide) followed by autologous stem cell transplantation may represent the best option, by curing about 50% of the patients whom such an approach can be applied to. Many new drugs have been proposed without achieving the expected results. Thus, the optimal treatment of PTCL_NOS remains unidentified.

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Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis

Cited by 21 publications

References 31 publications

Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis

Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis

Molecular diagnosis of T-cell lymphoma: a correlative study of PCR-based T-cell clonality assessment and targeted NGS

Peripheral T-Cell Lymphoma, Not Otherwise Specified: Clinical Manifestations, Diagnosis, and Future Treatment

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