Neuroblastoma Panel

Neuroblastoma is the most common type of childhood cancer that occurs before 1 year of age, accounting for 10-15% of cancer deaths in children. Approximately 90% of neuroblastomas are detected by 5 years of age, while 30% are found in the first year of life with the median age of diagnosis of 22 months (Esiashvili Natia et al. 2009). This tumor type can occur in adolescence and adulthood, although the prognosis is poorer compared to a childhood incidence (Colon and Chung 2011). The majority of neuroblastomas (65%) arise in the abdomen, with half of these in the medulla of the adrenal gland. They can also occur in the chest (20%), neck (5%), pelvis (5%), and in 1% of cases have an unknown primary (Colon and Chung 2011). Symptoms of patients with neuroblastoma include malaise, fevers, weight loss, enlarging mass, pain, and abdominal distention. Other symptoms can include early-onset hypertension and tachycardia due to the secretion of catecholamines. Neuroblastomas commonly occur sporadically in a family, but 1-2% of cases occur with family histories of neuroblastoma. Hereditary neuroblastomas tend to have earlier presentations and lead to multiple primary cancers. They also show significant clinical heterogeneity, whereby a pedigree may show an individual with spontaneous cancer regression, whereas another individual with metastatic spread (Deyell and Attiyeh 2011). Siblings of an affected patient with neuroblastoma have a 10-fold increase in developing neuroblastoma (Friedman 2005). Neuroblastomas can also be found with other conditions such as Hirschsprung disease, congenital hypoventilation disorder, and neurofibromatosis type 1 (Greengard and Park 2012).

Hereditary neuroblastoma is an autosomal dominant disorder that shows incomplete penetrance (Fisher and Tweddle 2012). Neuroblastomas show whole-chromosome gains and segmental chromosomal aberrations. The former results from hyperdiploidy and has a favorable prognosis, whereas the latter is associated with MYCN amplification and associated with worse outcomes (Colon and Chung 2011). The most frequent genetic aberration is an unbalanced chromosome 17q gain found in 70% of neuroblastomas, which has a poor prognosis (Bown et al. 1999).

In cases of hereditary neuroblastoma, the most common etiology are pathogenic variants in the anaplastic lymphoma kinase (ALK) oncogene. ALK encodes a tyrosine kinase receptor involved in cellular differentiation, proliferation, and survival. Pathogenic variants lead to constitutive activation of kinase activity. ALK pathogenic variants are rarely found in simplex cases (Mosse et al. 2008). All reported ALK causative variants have been missense, with the majority in the kinase domain (Human Gene Mutation Database).

Another cause of hereditary neuroblastomas are PHOX2B pathogenic variants, which are often associated with Hirschsprung's disease and/or congenital hypoventilation (Mosse et al. 2004). PHOX2B encodes a transcription factor that is involved in the normal sympathetic neuronal development and catecholamine synthesis. PHOX2B pathogenic variants are rarely found in sporadic neuroblastomas (van Limpt et al. 2004). The majority of causative PHOX2B variants include missense and small insertions and deletions (Human Gene Mutation Database).

Germline pathogenic variants in KIF1B in individuals with neuroblastoma and pheochromocytomas, and possibly nonneural tumors, have been reported (Schlisio et al. 2008; Yeh IT et al. 2008). The majority of KIF1B causative variants are missense changes (Human Gene Mutation Database).

Taken together, ALK and PHOX2B germline pathogenic variants account for 90% of hereditary neuroblastoma, with the majority being in the ALK gene (Fisher and Tweddle 2012).

Clinical sensitivity for KIF1B pathogenic variants is unknown at this time since relatively few individuals with these variants have been reported.

No gross deletions or duplications have been reported for these genes for neuroblastoma. They are expected to be rare.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Sanger sequencing of PHOX2B exon 3 for detection of the polyalanine repeat region is not performed as part of this test.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).