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Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project.

ABSTRACT: MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA.All clinical features (age ? 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ? 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P < .001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P < .001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations).MNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA.

SUBMITTER: Thompson D

PROVIDER: S-EPMC4777644 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project.

Thompson Daria D Vo Kieuhoa T KT London Wendy B WB Fischer Matthias M Ambros Peter F PF Nakagawara Akira A Brodeur Garrett M GM Matthay Katherine K KK DuBois Steven G SG

Cancer 20151228 6

<h4>Background</h4>MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.<h4>Methods</h4>Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patient ...[more]

PMID: 26709890

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Project description:Simple Summary MYCN gene amplification, the strongest prognostic marker of aggressive neuroblastoma, is detected on invasive biopsy tissues. This study aimed to establish a less invasive method to detect MYCN status based on MYCN mRNA contents in large extracellular vesicles or microvesicles. MYCN mRNA-containing microvesicles were detectable in three distinct MYCN-amplified neuroblastoma cell lines but absent in three neuroblastoma cells with MYCN-non-amplification. The feasibility of this EV-based workflow was successfully demonstrated by using the simulated samples (prepared by pulsing neuroblastoma MVs into the normal human serum) and bone marrow plasma specimens obtained from nine patients at various disease stages. Taken together, this study established the novel EV-based method for detecting MYCN status in pediatric neuroblastoma. Abstract MYCN amplification is the strongest predictor of high-risk neuroblastoma (NB). The standard procedure to detect MYCN status requires invasive procedures. Extracellular vesicles (EVs) contain molecular signatures of originated cells, present in biofluids, and serve as an invaluable source for cancer liquid biopsies. This study aimed to establish an EV-based method to detect the MYCN status of NB. Two EV subtypes, i.e., microvesicles (MVs) and exosomes, were sequentially isolated from the culture supernatant by step-wise centrifugation, ultrafiltration, and size-exclusion chromatography. Quantitative RT-PCR was performed to detect MYCN mRNA. As a result, MYCN mRNA was detectable in the MVs, but not exosomes, of MYCN-amplified NB cells. MYCN mRNA-containing MVs (MYCN-MV) were successfully detected in three distinct MYCN-amplified NB cell lines but absent in three MYCN non-amplification cells. The simulated samples were prepared by pulsing MVs into human serum. MYCN–MV detection in the simulated samples showed a less interfering effect from the human blood matrix. Validation using clinical specimens (2 mL bone marrow plasma) obtained from patients at various disease stages showed a promising result. Five out of six specimens of MYCN-amplified patients showed positive results, while there were no false positives in four plasma samples of the MYCN non-amplification group. This study communicated a novel EV-based method for detecting the MYCN status of pediatric NB based on MYCN mRNA contents in MVs. Future studies should be pursued in a prospective cohort to determine its true diagnostic performance.

Dataset Information

Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project.

Publications

Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project.

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