Hereditary Neuroblastoma via the PHOX2B Gene

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 et al. Curr Probl Cancer 33:333-60, 2009). This tumor type can occur in adolescence and adulthood, although the prognosis is poorer compared to a childhood incidence (Colon and Chung. Advances in Pediatrics 58:297-311, 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 1% of cases have an unknown primary (Colon and Chung. Advances in Pediatrics 58:297-311, 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. Cancer Genetics 204:113-121, 2011). Siblings of an affected patient with neuroblastoma have a 10-fold increase in developing neuroblastoma (Friedman et al. Cancer Epidemiol Biomarkers Prev 14:1922-7, 2005). Neuroblastomas can also be found with other conditions such as Hirschsprung disease, congenital hypoventilation disorder, and neurofibromatosis type 1 (Johnson and Park. "ALK-Related Neuroblastoma Susceptibility." GeneReviews, 2012).

Hereditary neuroblastoma is an autosomal dominant disorder that shows incomplete penetrance (Fisher and Tweddle. Seminars in Fetal & Neonatal Medicine 17: 207-215, 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. Advances in Pediatrics 58:297-311, 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. N Engl J Med 340:1954-1961, 1999). In cases of hereditary neuroblastoma the most common etiology are mutations in the anaplastic lymphoma kinase (ALK) oncogene. Another less frequent cause of hereditary neuroblastomas are from PHOX2B mutations, which are often associated with Hirschsprung's disease and/or congenital hypoventilation (Mosse et al. Am J Hum Genet 75:727-730, 2004). PHOX2B encodes a transcription factor that is involved in the normal sympathetic neuronal development and catecholamine synthesis. PHOX2B mutations are rarely found in sporadic neuroblastomas (van Limpt et al. Oncogene 23:9280-8, 2004). The majority of causative PHOX2B mutations include missense and small insertions and deletions (Human Gene Mutation Database).

Taken together, ALK and PHOX2B germline mutations account for 90% of hereditary neuroblastoma, with the majority being in the ALK gene (Fisher and Tweddle. Seminars in Fetal & Neonatal Medicine 17: 207-215, 2012).

This test provides full coverage of all coding exons of the PHOX2B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

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