Prognostic value of T-cell receptor γ rearrangement in peripheral blood or bone marrow of patients with peripheral T-cell lymphomas

Abstract

Design: Forty-five patients with SCCT were studied by immunohistochemistry to evaluate expression of EGFR, p-Akt and p-NF-κB. EGFR staining was performed using EGFR pharmDx kit on a Dako Autostainer. p-Akt and p-NF-κB were stained using a semi-automatic method (manual phospho-antibody incubation overnight, followed by automatic staining using a Dako autostainer). Results for SCCT were compared with those for associated high grade dysplasia (HGD) and adjacent normal appearing epithelium. In addition, tonsillar epithelium from non-neoplastic specimens of age-matched patients was also stained for the same markers. Results: In both HGD and SCCT, all three markers were overexpressed, when compared to those in the adjacent normal epithelium and the normal control tonsillar epithelium. When markers from SCCT were correlated with survival status, only p-NF-κB was a statistically significant predictor of poor survival (p=0.047). No markers in SCCT were significantly related to rate of recurrence. When analyzing marker scores from HGD tissue, both p-Akt (p=0.043) and p-NF-κB (p=0.006) were related to poor survival. Additionally, p-NF-kB from HGD tissue was related to rate of recurrence (p=0.049). Conclusion: p-NF-κB, overexpressed in HGD and SCCT, is associated with worse prognosis in terms of rate of recurrence and poor survival. This significant finding in patients with SCCT suggests that p-NF-κB represents a potential therapeutic target in head and neck squamous cell carcinoma (HNSCC). Background: In non-neoplastic T-cells, T-cell receptor (TCR) engagement induces activation of a cascade of membrane-associated and cytoplasmic kinases leading to widespread transcriptional changes that support cell survival and proliferation. The role of this important growth pathway in promoting T-cell tumors has not been well established. Design: Using phosphospecific antibodies as markers of kinase activation, we examined the expression and function of TCR-associated tyrosine kinases Lck, Syk and ZAP-70 as well as downstream Akt kinase in a wide range of T-cell neoplasms (n=158) and T-cell tumor lines (n=3). We evaluated the functional upregulation and expression of Akt and its target forkhead after TCR ligation. We examined the effect of blocking the proximal TCR signaling pathway on the expression/activation of Lck, Akt, and LAT using rosmarinic acid, a putative inhibitor of the TCR-associated kinase, Lck. Results: Nearly half (48%) of primary peripheral T-cell tumor samples showed constitutive activation of the TCR-associated kinases and downstream Akt, whereas most (57%) anaplastic large cell lymphomas showed absence of activated TCR-pathway components and much lower levels of Akt activation. Activation of the TCR-associated kinases and Akt in these tumors appeared to be independent of the presence or absence of surface TCR-CD3 complex suggesting a non-canonical mechanism of activation. These results were paralleled by in vitro stimulation studies in which some primary T-cell tumors and cell lines showed activation of TCR-associat...

Next-Generation Sequencing-Based Monitoring of Circulating Tumor DNA Reveals Clonotypic Heterogeneity in Untreated PTCL

“…In contrast, TCR gene rearrangement is one of the defining characteristics of all mature T-cell malignancies, with tumor tissue TCRɣ rearrangement detectable in 90% of patients. 44 When one-step and multiplex PCR assays were used for qualitative detection of TCRɣ rearrangements in FFPE the detection rate was 79% 12,45 compared to 86% of patients in our study with baseline FFPE samples in whom a clonotype was detected in both FFPE and serum.…”

“… 6-9 Furthermore, patient selection is largely empirical, highlighting the need for molecular tools for risk-adapted patient selection. Analyses of a mono- or oligoclonal T-cell population, including flow cytometry for TCRVβ and TCRβ constant region 1, 10,11 multiplex polymerase chain reaction (PCR) for TCRβ and TCRγ rearrangments, 12 and next-generation sequencing (NGS) of TCR complementarity-determining region 3 (CDR3) 13,14 can diagnose and provide prognostic information in PTCL but require circulating lymphoma cells, which limits broad applicability.…”

Clonal Rearrangements and Malignant Clones in Peripheral T-cell Lymphoma

“…Morphological methods failed to detect bone marrow involvement in four patients (№ 16–19), whereas PCR detected clonal cells in their bone marrow. Detection of clonal rearrangements of TCRG genes in the bone marrow or blood is considered to be a poor prognostic factor in PTCL [ 18 ]. In most patients, we observed multiple (more than two) clonal rearrangements in one locus.…”

Hemophagocytic lymphohistiocytosis and clonally related T‐cell malignancies in a pediatric patient

“…15 Patients in whom PTCL cells express a gamma/delta TCR carry a particularly poor prognosis. 16 Intriguingly, molecular and cytogenetic studies allowed us to determine that the PTCL cells shared clonal origins with the earlier T-ALL. While this appears to be rare, at least two adult patients have been reported who developed a clonally related PTCL after achieving complete remission from T-ALL, with similar immunophenotypic changes following this clonal transformation.…”