International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Abstract

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n ¼ 8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies.

ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients

“…This concept has been established for HER2 testing in breast cancer and MYCN testing in neuroblastoma, although the cutoffs used in our current study vary somewhat from those that define 'copy number gain' or 'amplification' in HER2 and NMYC testing. 25,26 We identified 54 RCCs with ALK copy number gain (Z5 copies). We also identified an association between the presence of Z5 copies of ALK and a poorer cancer-specific survival in patients with CCRCC but not in PRCC.…”

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

“…These tumours uniformly exhibit an immature cellular phenotype, reflecting their origin from early embryonic populations such as sympathoadrenal progenitors for neuroblastoma and metanephric progenitors for nephroblastoma. While many SRBCT subtypes exhibit characteristic chromosomal rearrangements [12][13][14][15][16] , next-generation sequencing studies have shown relatively few DNA sequence mutations in childhood cancers compared with adult neoplasms 8 . The present study of intratumoral heterogeneity in SRBCTs therefore focused on genomic aberrations larger than point mutations, that is, those detectable by high-resolution genotyping arrays.…”

The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins

“…Comparing the number of MYCN signals and centromere 2 signals, all cases were scored as MYCN-gained and none as MYCN amplified. 33 The proportion of neuroblasts with MYCN gain varied from case to case, ranging from 10% (case 6) up to 61% (case 3) with the remainder in the 22-48% range. Four of the cases with MYCN gain also showed gain in ganglion cells (cases 2, 4, 5, and 8) with up to 17 copies in 1 ganglion cell in case 4 and 10-15 copies in 40% ganglion cells in case 8 (Figure 1b), whereas the neuroblastoma component showed up to 5 copies of MYCN per neuroblast.…”