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

Abstract

We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, Δ, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, I-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 Δ and progression-free survival (PFS). NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their Δ values were correlated (Spearman = 0.67, < 0.0001), although bone marrow was 7.9 ± 0.5 stronger than blood When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity ( < 0.0001 and = 0.007). Bone marrow and blood Δ values correlated with PFS ( < 0.001; = 0.001) even when bone marrow was morphologically negative ( = 0.001; = 0.014). Multivariate analysis showed that bone marrow and blood Δ values were associated with PFS independently of clinical disease and gene status ( < 0.001; = 0.055). This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. .

Six‐gene Assay as a new biomarker in the blood of patients with colorectal cancer: establishment and clinical validation

“…Through cell spiking assay using different but known amounts of SW1116, SW48, HCA‐7, LoVo, SW620 and RKO cancer cells, and subsequent RT‐PCR, we successfully established the following CTC equations for CEA Gene Assay and Six‐gene Assay. Based on previous studies (Marachelian et al ., ; Vandesompele et al ., ), a summary ΔCt for the six tested genes was calculated by subtracting the GM of the Ct for two reference genes from the GM of the Ct for the six genes. With a direct correlation between CTC numbers and ΔCt (Six‐gene) value, this CTC quantitative equation and corresponding transformation table (Table ) allow us to calculate CTC numbers by the ΔCt (Six‐gene) value of unknown blood samples.…”

Long-term disease stabilization in a patient with relapsed neuroblastoma after allogeneic hematopoietic stem cell transplantation. Clinical case and literature review

“…Несмотря на использование интенсивной комплексной терапии, долгосрочная бессобытийная выживаемость (БСВ) у пациентов с НБ, относящихся к группе высокого риска, не превышает 40 % [2,3], а около 20 % из этой группы развивают первичную резистентность к терапии (точная оценка затруднена тем, что до недавнего времени отсутствовали универсальные критерии резистентности [4]). Персистирование опухолевых клеток, выявляемое любым из методов, ассоциировано с крайне неблагоприятным прогнозом заболевания [5]. Кроме того, на основании ряда клинических и биологических факторов можно выделить группу ультравысокого риска, долгосрочная БСВ в которой не превышает 5 % [6].…”

The challenge of defining “ultra‐high‐risk” neuroblastoma

“…For example, high levels of tyrosine hydroxylase (TH) and paired‐like homeobox 2b (PHOX2B) mRNA in peripheral blood at diagnosis is strongly associated with inferior EFS and OS, identifying an UHR group representing 19% of patients with 5‐year EFS of 0% . Similarly, a 5‐gene mRNA assay is prognostic in patients being treated for relapsed/refractory NBL . At present, these different biomarkers have not been assessed in a multivariable analysis, so it is unknown whether they identify differential patient subsets or are surrogates for other prognostic factors.…”

“…19 Similarly, a 5-gene mRNA assay is prognostic in patients being treated for relapsed/refractory NBL. 20 At present, these different biomarkers have not been assessed in a multivariable analysis, so it is unknown whether they identify differential patient subsets or are surrogates for other prognostic factors. For example, at the end of induction it is likely that those with residual MIBG-avid lesions will overlap to a significant extent with MRD-positive cases.…”