The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report

University of Cologne, Köln, North Rhine-Westphalia, Germany
Journal of Clinical Oncology (Impact Factor: 18.43). 01/2009; 27(2):289-97. DOI: 10.1200/JCO.2008.16.6785
Source: PubMed


Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification.
The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors.
Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively.
By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

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    • "Owing to the strong co-occurrence of MNA and 1p loss (Cohn et al., 2009), identifying the lesion from which the coherently increased expression is likely to have originated is not obvious. Our approaches allowed us to robustly associate the gene expression signature with 1p loss, but not with MNA. "

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    • "Peripheral neuroblastic tumours (pNTs, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) are the most common extra-cranial tumours of childhood, accounting for 15% of childhood cancer mortality, and 650–700 cases are newly diagnosed each year in the United States. Patients with pNTs are classified into three risk groups (low, intermediate, and high) based on the combination of prognostic factors, including clinical stage, age at diagnosis, histopathology, MYCN proto-oncogene status, DNA index, and other chromosomal abnormalities (Brodeur et al, 1984, 1993; Shimada et al, 1999a,b; Weinstein et al, 2003; Maris et al, 2007; Cohn et al, 2009). Among these factors, MYCN amplification, which is detected in about 20% of all pNTs, is considered as the most reliable genomic hallmark of aggressive clinical behaviour (Brodeur et al, 1984; Seeger et al, 1985; Goto et al, 2001). "
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    ABSTRACT: MYCN amplification with subsequent MYCN protein overexpression is a powerful indicator of poor prognosis of neuroblastoma patients. Little is known regarding the prognostic significance of the homologous MYC protein expression in neuroblastoma. Immunostaining for MYCN and MYC protein was performed on 357 undifferentiated/poorly differentiated neuroblastomas. Results were analysed with other prognostic markers. Sixty-seven (19%) tumours were MYCN(+), 38 (11%) were MYC(+), and one(0.3%) had both proteins(+). MYCN(+) tumours and MYC(+) tumours were more likely diagnosed in children>18months with stage4-disease. MYCN(+) tumours were associated with amplified MYCN, Unfavourable Histology (UH), and High-MKI (Mitosis-Karyorrhexis Index). MYC(+) tumours were also frequently UH but not associated with MYCN amplification, and more likely to have low-/intermediate-MKI. Favourable Histology patients without MYC/MYCN expressions exhibited the best survival (N=167, 89.7±5.5% 3-year EFS, 97.0±3.2% 3-year OS), followed by UH patients without MYC/MYCN expressions (N=84, 63.1±13.6% 3-year EFS, 83.5±9.4% 3-year OS). MYCN(+)patients and MYC(+)patients had similar and significantly low (P<0.0001) survivals (46.2±12.0% 3-year EFS, 63.2±12.1% 3-year OS and 43.4±23.1% 3-year EFS, 63.5±19.2% 3-year OS, respectively). Notably, the prognostic impact imparted by MYC expression was independent from other markers. In this series, ∼30% of neuroblastomas had augmented MYCN or MYC expression with dismal survivals. Prospective study of MYC/MYCN protein expression signature as a new biomarker for high-risk neuroblastomas should be conducted.British Journal of Cancer advance online publication, 2 June 2015; doi:10.1038/bjc.2015.188
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    • "2012). Features like age of the patient at diagnosis, stage of the disease, and nonrandom chromosomal aberrations are well-established parameters for stratification of risk and treatment as well as for predicting the disease outcome in patients (Cohn et al., 2009; Monclair et al., 2009). Neuroblastoma patients with nonrandom chromosomal alterations MNA (MYCN amplification )/1p (shorter arm of the chromosome 1) deletion/17q (longer arm of the chromosome 17) gain (seen in 20% of patients) or 11q deletion (11q-) /17q gain (seen in 30% of patients) are often associated with high-risk tumors and an unfavorable outcome. "
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    ABSTRACT: Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors. Copyright © 2014 Elsevier Inc. All rights reserved.
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