clinical This tumour of developing postganglionic sympathetic neurons occurs in the adrenal medulla or paraspinal ganglia and is the most common solid extracranial tumour in children. Most tumours arise in the abdomen. Mean age at diagnosis is 1.5 years and 90% of cases occur before the age of 10 years. The prognosis is variable with survival ranging from 95% to 50% in low- and high- risk groups, respectively. A variety of clinical, pathological, and molecular characteristics (e.g. age at diagnosis, histopathology, tumour MYCN amplification, and chromosomal deletions) are used to categorize affected children into several groups (low to ultra- high) and guide management. A striking feature of neuroblastoma in some patients (particularly young infants) is spontaneous regression, even if meta static disease is present. Most cases are sporadic and familial cases are rare (up to 2% of all cases) but have provided important insights into the molecular basis of this disorder.
Genetics of Familial neuroblastoma
Inherited susceptibility to neuroblastoma may be occur as part of well- recognized syndromes such as Beckwith– Wiedemann syndrome and hemihypertrophy, NF1 and RASopathy disorders, congenital central hypoventilation syndrome (Ondine’s course) and Hirschsprung disease. In addition, familial (non- syndromic) neuroblastoma may be inherited as an autosomal dominant trait with incomplete penetrance.
Genetic linkage studies in kindreds with familial non- syndromic neuroblastoma localized a gene to chromosome 2p23– p24 and sequencing of the ALK (anaplastic lymphoma kinase) proto- oncogene identified recurrent missense variants that act as activating mutations in the ALK tyrosine kinase domain. Germline pathogenic variants in ALK are found in about 80% of familial neuroblastoma kindreds. In addition, about 10% of sporadic neuroblastomas harbour somatic ALK mutations. Functional studies of mutant ALK have identified genotype- phenotype- functional correlations such that the familial mutations with stronger activating effects (e.g. R1275Q) are associated with more complete penetrance than those with weaker activating effects (G1128A) and somatic mutations with the strongest activating effects (e.g. F1174* and F1245*) have only very rarely been detected in the germline but were associated with severe neurodevelopmental anomalies.
Idiopathic congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominantly inherited disorder characterized by abnormal autonomic control of ventilation resulting in cyanosis and hypercapnia during sleep. Additional features may include Hirschsprung disease and other features of autonomic nervous system dysfunction (excessive sweating, pupillary abnormalities, disordered body temperature regulation, etc.). Though the disorder may be fatal in the neonatal period, long- term survivors have been reported. CCHS is the most frequent syndromic cause of neuroblastoma and, in 2003, idiopathic CCHS was shown to be as sociated with germline mutations in the paired- like homeobox gene PHOX2B.
RASopathy disorders comprise a group of rare congenital syndromes that result from mutations in genes that encode com ponents of the RAS signalling pathway. These disorders include Costello syndrome (caused by activating mutations in the HRAS proto- oncogene), Noonan syndrome (PTNP11, KRAS, NRAS, SOS1, BRAF, RAF1, MEK1, RIT1), Cardiofaciocutaneous syndrome (BRAF, MAP2K1, MAP2K2, KRAS) and NF1. Of these disorders, the cancer risk is highest in Costello syndrome, which is characterized by developmental delay, short stature (though birth weight may be increased), facial dysmorphisms, and cardiac anomalies.
Beckwith– Wiedemann syndrome (BWS) is a congenital dis order characterized by variable features including macroglossia, anterior abdominal wall defects, pre- and/ or postnatal overgrowth, neonatal hypoglycaemia, lateralized overgrowth (hemihypertrophy and embryonal tumour predisposition in 5– 10% of cases. BWS is a human imprinting disorder that is characterized by altered expression/ function of the IGF2 growth suppressor and/ or the CDKN1C growth suppressor. BWS can be caused by several molecular mechanisms and the embryonal tumour risk varies between molecular subgroups. Overall, the most common embryonal tumour as sociated with BWS is Wilms tumour, but the neuroblastoma is the most frequent tumour in children with germline CDKN1C mutations (~4% of cases).
Neuroblastoma has been associated with germline TP53 mutations in a few cases (though neuroblastoma is not considered a characteristic Li- Fraumeni syndrome tumour) and rarely has occurred with a germline SDHB mutation. In addition, investigations of familial neuroblastoma to identify rare variants in inherited neuroblastoma genes, investigators have undertaken genome- wide association studies (GWAS) in sporadic cases to identify common variants predisposing to neuroblastoma variants. More than 15 susceptibility loci have been identified including variants at (or close to) BARD1, MLF1, CPZ, CASC15, LIN28B, LMO1, HSD17B12, and TP53. Several of the genes linked to neuroblastoma susceptibility by GWAS studies have also been implicated in tumour behaviour.
Somatic Genetics of neuroblastoma
More than 30 years ago, amplification of the MYCN proto- oncogene was identified as a key driver of neuroblastoma oncogenesis. MYCN amplification is associated with advanced tumour stage and poorer patient survival and evaluation of tumour NMYC status is a key component of pretreatment evaluation protocols that use clinical and biological data to categorize patients into the risk groups that determine individual clinical management. A number of recurrent copy number abnormalities have been described in neuroblastoma including loss of 1p, 4p, 6q, 11q, and 14q and gain at 1q, 2p, and 17q. Loss of 1p and 11q are features of high risk neuroblastoma but whereas 1p loss and 17q gain are correlated with MYCN amplification, 11q loss is inversely correlated with MYCN amplification [35]. Other somatic findings in neuroblastoma include ALK amplification (ALK and MYCN are both map to 2p24) and mutations, ATRX, ARID1A, and ARID1B mutations, and TERT promoter rearrangements. Though investigation for tumour MYCN status and copy number abnormalities (e.g. 11q loss) is routinely performed to establish risk group and guide treatment, other genomic profiling investigations (e.g. ALK mutation analysis) are not universal though will likely be adopted as targeted therapies become available. A well- recognized feature of neuroblastoma is the occurrence of spontaneous regression in a subset of cases. Several mechanistic aetiologies have been suggested but no genomic biomarker has been identified to date to predict which cases will regress.
Genetic testing and Surveillance
In non- syndromic patients, testing for germline mutations associated with inherited neuroblastoma is indicated if there is a family history of neuroblastoma or if there are multifocal or bilateral tumours. In addition, the presence of clinical features of a syndrome associated with neuroblastoma predisposition is an indication for specific genetic testing to be initiated.
The neuroblastoma risk in individuals with a germline ALK or PHOX2B mutation has been estimated at up to 50% and such individuals should be offered regular surveillance as recommended by AACR Childhood Cancer Predisposition Group and including abdominal ultrasound, measurement of urinary catecholamine metabolites (VMA and HVA) and chest radiography until age 10 years. An International Consensus Group recommended three monthly abdominal ultrasound scans until age 7 years in children with BWS and a CDKN1C mutation. Routine screening for neuroblastoma is generally not indicated in RASopathy disorders but should be considered in Costello syndrome (though elevated urinary VMA and HVA can occur in the absence of a tumour). About 15% of cases of familial neuroblastoma do not have an identifiable germline mutation and surveillance should also be considered for at risk children with a strong family history.
