Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma

Abstract

PurposeThe purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma.Materials and MethodsTH mRNA expression in PB was measured by reverse transcription quantitative real-time polymerase chain reaction in 210 patients who were newly diagnosed with neuroblastoma from July 2005 to June 2015 and the clinical significance of TH expression in PB at diagnosis was evaluated.ResultsTH expression was positive in 60 patients (28.6%). Fifty of 60 TH-positive patients had metastatic tumors and the remaining 10 had localized tumors. TH expression was associated with high-risk features (i.e., advanced stage, older age, unfavorable pathology, and MYCN amplification) at diagnosis. Among TH-positive patients, higher TH expression level was observed in high-risk patients than in low- or intermediate-risk patients (p=0.035). The probability of 5-year progression-free survival (PFS) was lower in TH-positive patients than in TH-negative patients (63.8±6.9% vs. 94.7±2.1%, p < 0.001). In analysis confined to high-risk patients, the 5-year probability of PFS remained lower in TH-positive patients (55.7±8.2% vs. 89.6±5.8%, p < 0.001). Among TH-positive patients, a higher expression level of TH was associated with a worse outcome. In multivariate analyses, positive TH expression in PB at diagnosis was an independent poor prognostic factor for PFS.ConclusionThe treatment intensity should be tailored according to TH expression in PB at diagnosis.

Risk stratification of high‐risk metastatic neuroblastoma: A report from the HR‐NBL‐1/SIOPEN study

“…Importantly, to provide sufficient follow-up data, the analy- Many studies have explored potential methods of identifying HR-NBL patients with particularly poor outcomes. These include quantification of tumour-related mRNA in blood or BM samples, 10,26,27 semi-quantitative scoring of mIBG response, 8,9,28 identification of specific tumour genetic aberrations such as ALK mutation or TERT rearrangements [29][30][31] and multiple different gene expression classifiers. [32][33][34] As yet, these techniques have not yet been simultaneously evaluated in sufficiently large homogeneously treated HR-NBL patient populations.…”

Favorable prognostic role of tropomodulins in neuroblastoma

“…Biochemical analysis evidenced a decrease of neuronal biomarkers expression and a significant increase of TH, DBH, NSE and CgA, indexes of neuroendocrine differentiation and considered unfavorable prognostic neuroblastoma biomarkers [ 34 ]. In a recent study, Lee and colleagues [ 35 ] evaluated the clinical significant of TH mRNA transcripts levels in the peripheral blood of patients with neuroblastoma demonstrating that TH expression was associated with high-risk features, advanced stage and worse outcome. Previous studies also reported that positive TH expression was a poor prognostic indicator in metastatic neuroblastoma [ 36 , 37 ], suggesting a role of this marker in stratification.…”

Opportunities and challenges of circulating biomarkers in neuroblastoma

“…As with immunocytochemical analyses, RT-PCR-based studies have consistently identified NB-specific mRNA in peripheral blood at diagnosis in patients with metastatic disease and in a fraction of patients with localized and stage 4S disease (table 4). Diagnostic TH mRNA levels and CTC counts are typically higher in patients with more advanced metastatic disease [185,204,206,212] and in patients with high-risk disease [206,212], as observed in other solid malignancies [166]. However, NB-specific mRNA levels and CTC counts do not correlate with MYCN status [182,184,206,207,212].…”

“…In addition to serving as a potential diagnostic biomarker, there is a wealth of evidence supporting the prognostic value of NB-specific mRNA, with numerous studies reporting a correlation between mRNA levels and survival outcomes (table 4). High transcript levels of TH and other NB-specific genes at diagnosis have been associated with poor OS and/or EFS in patients with localized and metastatic disease, independent of risk status [187,193,194,197,203,206,208]. Similarly, high CTC counts (≥ 10 cells per 4 ml blood) have recently been shown to correlate with poor OS [212].…”

“…No significant correlations with EFS were made after induction therapy.Lee et al . [206]RT-qPCR CHGA, DCX, DDC, PHOX2B, TH NDNB-mRNA detectable in patients with relapsed/refractory disease. Lower RT-qPCR ΔC T values correlated with poorer PFS, independent of disease stage or MYCN status.Marachelian et al .…”