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Abstract
We previously developed a method for determining MYCN gene amplification status using cell-free DNA fragments released from cancer cells into the blood of patients with neuroblastoma (NB). Here, we analyzed the relationship between MYCN amplification (MNA) status and neuroblastoma prognosis. We screened serum samples from 151 patients with NB for MNA, using real-time quantitative PCR, and compared the results with MYCN status determined using paired tumor samples. We additionally investigated whether MNA status correlates with patient survival. When a cut-off value of 5 was used, serum-based MNA analysis was found to show good sensitivity (86%) and very high specificity (95%). The sensitivities for stage 1 and 2 might be acceptable, even though it is not as good as for stage 3 and 4 (67% for stage 1 and 2, 92% for stage 3, and 87% for stage 4). MNA status correlated with overall survival in our cohort of 82 patients, with survival data available (p < 0.01). The hazard ratio of MNA status was 4.98 in patients diagnosed at less than 18 months of age (95% confidence interval, 1.00–24.78), and 1.41 (95% confidence interval, 0.63–3.14) for those diagnosed at 18 months of age or older. Serum-based MNA analysis is rapid and non-invasive compared with tumor-based MNA analysis, and has potential to predict tumor MNA status. There is still a room to improve the sensitivity of the test for tumors of stages 1 and 2, nonetheless this assay might help to determine therapeutic strategies prior to tumor biopsy, especially for patients with a life-threatening condition, as well as for patients of less than 18 months of age whose risk-grouping and treatment allocation depends on their MNA status.
Highlights
Patients with neuroblastoma (NB) fall into 2 clinically distinct subgroups: a low-risk subgroup and a high-risk subgroup based on their age of onset [1], the extent of the disease [2], pathological findings [3], and genomic changes in NB tumors
The application of the present findings to population-screening programs requires improvement in the sensitivity of the detection method especially for the patients with low-stage NB; the present assay should be useful for the design of therapeutic strategies for patients with NB prior to a tumor biopsy, especially for patients with a life-threatening condition and those less than 18 months of age, whose risk grouping and treatment allocation depends on their MYCN amplification (MNA) status
The advantages of this method for preoperative evaluation of MNA status are that it (1) benefits patients with NB, including children, by enabling rapid determination of MNA status prior to biopsy or surgical resection, (2) involves no procedures that are laborious for pediatric surgeons and oncologists or hazardous for patients, and (3) requires only 200 μL
Summary
Patients with neuroblastoma (NB) fall into 2 clinically distinct subgroups: a low-risk subgroup and a high-risk subgroup based on their age of onset [1], the extent of the disease [2], pathological findings [3], and genomic changes in NB tumors. A screening test for NB has been designed with the aim of enabling early intervention and consequent improvement in survival in patients with NB. This nationwide screening system, which was launched in Japan in 1973 and later introduced in other countries [4, 5], has facilitated the detection of NB in numerous patients of less than one year of age prior to the overt clinical manifestation of symptoms. 2 prospective studies concluded that detection of subclinical NB by mass screening did not reduce overall mortality in patients with this disease [11, 12]. Recent efforts have focused on the development of novel, clinically useful, and cost-effective NB screening systems to enable improvements in outcome for patients with NB
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