What are the chromosomal and molecular markers of pediatric neuroblastoma?

Updated: Oct 09, 2017
  • Author: Norman J Lacayo, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Answer

Over the last 2 decades, many chromosomal and molecular abnormalities have been identified in patients with neuroblastoma. These biologic markers have been evaluated to determine their value in assigning prognosis, and some of these have been incorporated into the strategies used for risk assignment.

The most important of these biologic markers is MYCN. MYCN is an oncogene that is overexpressed in approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. This gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage disease. Patients whose tumors have MYCN amplification tend to have rapid tumor progression and poor prognosis, even in the setting of other favorable factors such as low-stage disease or 4S disease.

In contrast to MYCN, expression of the H-ras oncogene correlates with lower stages of the disease. Cytogenetically, the presence of double-minute chromatin bodies and homogeneously staining regions correlates with MYCN gene amplification. Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastoma and confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or genes that control neuroblast differentiation. Deletion of 1p is more common in near-diploid tumors and is associated with a more advanced stage of the disease. Most of the deletions of 1p are located in the 1p36 area of the chromosome.

A relationship between 1p loss of heterozygosity (LOH) and MYCN amplification has been described. Other allelic losses of chromosomes 11q, 14q, and 17q have been reported, suggesting that other tumor suppressor genes may be located in these chromosomes. Loss of heterozygosity at 11q23 has been described and is an independent prognostic factor. Another characteristic of neuroblastoma is the frequent gain of chromosome 1.

DNA index is another useful test that correlates with response to therapy in infants. Look et al. demonstrated that infants whose neuroblastoma have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to cyclophosphamide and doxorubicin. [1] In contrast, infants whose tumors have a DNA index of 1 are less responsive to the latter combination and require more aggressive therapy. DNA index does not have any prognostic significance in older children. In fact, hyperdiploidy in children more frequently occurs in the context of other chromosomal and molecular abnormalities that confer a poor prognosis.

Three neurotrophin receptor gene products, TrkA, TrkB, and TrkC, are tyrosine kinases that code for a receptor of members of the nerve growth factor (NGF) family. Their ligands include p75 neurotrophin receptor (p75NTR) NGF, and brain-derived neurotrophic factors (BDNFs). Interestingly, TrkA expression is inversely correlated with the amplification of the MYCN gene, and the expression of the TrkC gene is correlated with TrkA expression. In most patients younger than 1 year, a high expression of TrkA correlates with a good prognosis, especially in patients with stages 1, 2, and 4S. In contrast, TrkB is more commonly expressed in tumors with MYCN amplification. This association may represent an autocrine survival pathway.

Disruption of normal apoptotic pathways may also play a role in neuroblastoma pathology. Disruption of these normal pathways may play a role in therapy response as a result of epigenetic silencing of gene promoters in apoptotic pathways. Drugs that target DNA methylation, such as decitabine, are being explored in preliminary studies.

Other biologic markers associated with poor prognosis include increased levels of telomerase RNA and lack of expression of glycoprotein CD44 on the tumor cell surface. P-glycoprotein (P-gp) and multidrug resistance protein (MRP) are 2 proteins expressed in neuroblastoma. These proteins confer a multidrug-resistant (MDR) phenotype in some cancers. Their role in neuroblastoma is controversial. Reversal of MDR is one target for novel drug development.

A study by Challagundla et al reported that exosomic microRNAs released within the neuroblastoma environment affect resistance to chemotherapy. [2]


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