Segmental chromosomal aberrations (SCAs)

The SCAs frequently observed in neuroblastoma and used when assigning SCA status include losses of or at chromosome arms 1p, 3p, 4p, and 11q and gains of or at chromosome arms 1q, 2p, and 17q.[8] These alterations can be detected by multiple methods, including fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next-generation sequencing (NGS) assays. SCAs are present in most high-risk and/or stage 4 neuroblastoma tumors.[3,4,6,7,9] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of SCAs) correlated with the following:[3-7][Level of evidence C2]

Determining the presence of SCAs is potentially clinically useful. Detecting SCAs can help distinguish patients with clinically favorable presentation who are at higher risk of treatment failure. Examples are provided below.

In an analysis of localized, resectable, non-MYCN amplified neuroblastoma, cases from two consecutive European studies and a North American cohort (including International Neuroblastoma Staging System [INSS] stages 1, 2A, and 2B) were analyzed for selected SCAs (namely loss of 1p, 3p, 4p, and 11q and gain of 1q, 2p, and 17q). The study revealed a different prognostic impact of tumor genomics depending on patient age (<18 months vs. >18 months) and stage (1 vs. 2). Patients were treated with surgery alone regardless of a tumor residuum.[10][Level of evidence C1]

In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, SCAs were found in most patients. Older children were more likely to have them and to have more SCAs per tumor cell. In children aged 12 to 18 months, the presence of SCAs had a significant effect on EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with SCAs (67%) and children without SCAs (100%), regardless of tumor histology.[7]

SCAs were also found to be predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[1,2] An analysis of 133 patients (aged ≥18 months) with INSS stage 3 tumors without MYCN amplification demonstrated that SCAs were associated with inferior EFS, and chromosome 11q loss was independently associated with worse OS.[11]

Chromosome 11q loss occurs in approximately 30% of high-risk neuroblastoma cases, but it is uncommonly observed in tumors with MYCN amplification.[3] Chromosome 11q loss is frequently observed in high-risk neuroblastoma cases with either TERT rearrangements or with ALT pathway activation.[12,13] Chromosome 11q loss has also been associated with inferior EFS and poor response to induction therapy in patients with high-risk neuroblastoma, as described below:

Distal chromosome 6q losses have also been associated with poor outcome. An international collaboration studied 556 patients with high-risk neuroblastoma. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%.[16] A second study confirmed the very poor prognosis of patients with high-risk neuroblastoma who have distal 6q loss. Pooling across both studies, MYCN amplification occurred in only 20% of cases with distal chromosome 6q loss.[17]

The same study of 556 patients with high-risk neuroblastoma that identified poor prognosis for patients with distal 6q loss also evaluated amplifications of regions not encompassing the MYCN locus. Regions of non-MYCN amplification were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[16]