Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

Purpose: We determined if quantifying neuroblastoma (NB)-associated mRNAs (NB-mRNA) in bone marrow (BM) and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory NB. <br /><br />Patients and Methods: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in BM and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold [Ct] for the geometric mean of genes from the TaqMan® Low Density Array NB5 assay) and morphologically-defined tumor cell percentage in BM, ¹²³I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between DCt and progression-free survival (PFS). <br /><br />Results: NB-mRNA was detectable in 83% of BM (185/223) and 63% (89/142) of blood specimens, and their DCts were correlated (Spearman r=0.67, p<0.0001) although BM Ct was 7.9±0.5 Ct stronger than blood Ct. When BM morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of BMs. When all three were negative, NB-mRNA was detected in 55% (11/20) of BMs. BM NB-mRNA correlated with BM morphology or MIBG positivity (p<0.0001 and p=0.007). BM and blood Cts correlated with PFS (p<0.001; p=0.001) even when BM was morphologically negative (p=0.001; p=0.014). Multivariate analysis showed that BM and blood Cts were associated with PFS independently of clinical disease and MYCN gene status (p<0.001; p=0.055). <br /><br />Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory NB.

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