Home About Research Programs & Laboratories The Maris Laboratory & Research Program

Research Programs & Laboratories

The Focus of our Research

Dr. Maris' laboratory is dedicated to translating basic science discoveries into improved treatment approaches for childhood cancers. By focusing on the pediatric cancer neuroblastoma, Dr. Maris had developed a translational genomics laboratory that has delivered new biomarkers and novel therapies to the clinic.

The Focus of our Research

Dr. Maris' laboratory is dedicated to translating basic science discoveries into improved treatment approaches for childhood cancers. By focusing on the pediatric cancer neuroblastoma, Dr. Maris had developed a translational genomics laboratory that has delivered new biomarkers and novel therapies to the clinic.

Clinical Research

The Children's Hospital of Philadelphia has developed a specialized program for treating patients with neuroblastoma. Patients newly diagnosed with the disease are generally treated by the Children's Oncology Group (COG). Patients with the aggressive form of the disease may be treated on institutional protocols under the direction of Stephan Grupp, MD, PhD. For patients with relapsed or refractory disease, we have developed a team of investigators dedicated to providing options for families. There is an evolving portfolio of clinical trials from various sources, detailed below, that may be open and available. Consultation with the Neuroblastoma Developmental Therapeutics Team is required to determine eligibility and suitability for any trial. After consultation, the team can develop and provide a recommendation for the referring physician.

Basic and Translational Research


Project 1: Identification of the Hereditary Neuroblastoma Predisposition Gene

Like all human cancers, a small percentage of neuroblastomas are inherited. We have had a program for over 15 years to collect specimens from these rare families, as well as other children presumed to have genetic susceptibility to develop this disease (1-4). We previously showed that mutations in the homeobox gene PHOX2B occur in complex cases of sporadic and hereditary neuroblastoma that co-occur with other diseases of neural crest tissues such as Hirschsprung disease and congenital central hypoventilation syndrome (5, 6). Through an international collaborative effort, we have recently completed a high resolution whole genome scan with 6000 SNPs, and discovered a locus on chromosome 2p that is highly likely to contain the familial neuroblastomagene. Because this is a region that is frequently gained somatically, we hypothesize that it will be an oncogene. We recently discovered germline mutations segregating with neuroblastoma pedigrees in one such gene, and these data will be reported at the American Association for Cancer Research Meeting in April 2008. Future work will focus on characterizing the mutation spectrum of this recently identified gene in familial and sporadic cases, understanding the functional consequences of these mutations, and developing strategies for diagnostics and therapeutics.

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Project 2: The Genetic Basis of Neuroblastoma Tumorigenesis: A Genome-wide association study (GWAS) approach

Project 1 is focused on discovering the rare mutations that provide a very high likelihood for developing neuroblastoma. Like breast cancer and other human malignancies, these mutations are likely to account for only a small fraction of all cases. Thus, we hypothesize that common variations in the human genome can also influence susceptibility to develop neuroblastoma. We therefore are engaged in a GWAS enabled efforts through the Children's Oncology Group (www.childrensoncologygroup.org) to collect thousands of DNA samples from neuroblastoma patients. We ultimately will genotype 5000 neuroblastoma cases at over 550,000 single nucleotide polymorphisms, and compare these data to a larger group of children without cancer collected as part of the Center for Applied Genomics (link for Center for Applied Genomics) ongoing program to genotype over 100,000 children from the Children's Hospital of Philadelphia. We recently completed an interim analysis that provides critical proof-of-concept. After genotyping the first 1032 subjects, we identified a highly significant association signal that has now been replicated in three separate cohorts (30). In addition, we have discovered another strong association signal within a known Tumor Suppressor Gene when one limits the analytic cohort to children with the high-risk form of the disease. Finally, instead of looking at genotypes, we also performed an analysis restricted to copy number variation in the human genome. We discovered several strong association signals, two of which show robust replication (some of the others may require additional cases and controls, and these are being added). Ongoing work is focused on understanding the underlying genetic alterations that are driving these association signals while also building up the case-series to discover additional loci.

External data links: GWAS Phase 1 Discovery case-series

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Project 3: Significance of Genetic Alterations in Neuroblastoma

Neuroblastoma is a disease that has very diverse clinical features, with about a third of cases being extremely benign and easily cured, while about half of cases are very aggressive with cure rates below 40%. Our lab has had a long-standing interest in defining the genetic correlates of this clinical behavior (7-13). This project focuses on genome-wide approaches to discover recurrent somatically acquired alterations in tumors obtained at diagnosis through the Children's Oncology Group. Project 4-6 have evolved out of these efforts as we have shown that there are patterns at the DNA and RNA levels that are strong predictors of phenotype. The current focus of this project is to develop a chip-based molecular diagnostic assay to reliably predict neuroblastoma clinical course (14). We will utilize a SNP-based system, and plan for this to be the assay that will be done on all newly diagnosed neuroblastoma patients in the COG that will allow for individualization of treatment planning.

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Project 4: Genomics and Epigenomics of Human Neuroblastoma

One of the more common recurrent alterations in high-risk neuroblastomas is deletion of chromosome 3p (7, 9). This project is designed to discover the Tumor Suppressor Genes located at 3p that are inactivated during the malignant evolution of these tumors. Regions of interest are mapped using high-resolution array based methodologies and highly annotated tumor samples. Genes within these regions are subjected to resequencing to identify putative inactivating alterations. In addition, we have strong preliminary evidence that several genes in our regions of interest may be functionally inactivated via epigenetic mechanisms such as hypermethylation. Thus, ongoing and future work will focus on integration of genomic and epigenomic data sets, both focused on 3p as well as genome-wide.

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Project 5: Discovery of Chromosome Arm 11q Tumor Suppressor Genes in Neuroblastoma

We recently showed that deletion of the long arm of chromosome 11 is a very powerful biomarker for outcome in newly diagnosed neuroblastoma patients (11). This has now been incorporated into a prospective clinical trial in the Children's Oncology Group focused on children with intermediate-risk neuroblastoma (those with a clinical course most difficult to predict). This project now focuses on discovering the Tumor Suppressor Genes that are targeted by these chromosomal deletions. We have mapped regions of interest using high density SNP arrays, and hypothesize that several genes are likely involved since the fast majority of the deletions are very large. Current work is focused on resequencing lead candidates as well as functional replacement of full length cDNAs of these candidates into relevant cell line models.

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Project 6: The Therapeutically Applicable Research to Generate Effective Treatments (NBL-TARGET) Initiative

This multi-institutional collaborative project is designed to use cancer genomics and resequencing efforts to discover neuroblastoma oncogenes and tumor suppressors that can be leveraged therapeutically. In collaboration with the NCI Cancer Genome Atlas project (http://cancergenome.nih.gov/), investigators at CHOP, the Children's Hospital Los Angeles, the Oncogenomics Branch of the NCI and the Children's Oncology Group have identified over 400 highly annotated and carefully selected diagnostic human neuroblastoma samples. Each sample will be assayed using a 550K SNP platform for copy number alterations and LOH, and also on an exon-based expression array. The aggressive timeline will result in a minimum of 100 candidate genes identified from regions of interest emerging through an integrative analysis for complete resequencing of coding regions.

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Project 7: Discovery of novel therapeutic strategies for human neuroblastoma

The Children's Hospital of Philadelphia holds a Program Project Grant focused on determining the underlying biology of human neuroblastoma for the purpose of improving therapy. Dr. Garrett Brodeur is the overall PI, and his project focuses on the role of neurotrophin receptors and their ligands in neuroblastomas. A phase 1 clinical trial through the NANT consortium (www.nant.org) with a targeted inhibitor of this pathway is ongoing. Dr. Michael Hogarty leads a project focused on understanding how the MYCN oncogene leads to a more aggressive clinical phenotype, and how cancer cells adapt to highly abnormal expression of the MYCN protein. Dr. Peter Adamson's lab is determining how best to utilize retinoids in neuroblastoma therapy, and how best to integrate these compounds with other chemotherapies. The Maris lab has a project focused on antiangiogenic strategies for neuroblastoma therapy. The major goal is to understand which pro- and anti-angiogenic genes are dysregulated during neuroblastoma initiation and progression, and how to utilize this knowledge therapeutically (8, 15-19). We utilize mouse models and human tumor samples to study changes in gene expression associated with tumor growth and metastasis. The lab is also responsible for the animal and pathology core, and Dr. Bruce Pawel leads efforts in advanced immunohistochemistry and in the development, use and interpretation of a large neuroblastoma tumor microarray. More recently, we have applied our model systems to discover other therapeutically relevant drug targets in other biologically relevant pathways.

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Project 8: Pediatric Preclinical Testing Program

The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenograft and cell lines to use for in vivo and in vitro testing. These include tumors of the kidney, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), and rhabdoid tumors (CNS and renal). There is also a detailed molecular profiling of each xenograft to help in prioritization and follow-up studies (manuscript in press). The Maris lab is responsible for the neuroblastoma xenograft panel, and we screen on average one drug per month in six or more xenograft models. This program has been highly efficient, and anti-tumor activity against neuroblastoma in these models for a variety of agents is now known (20-29). Potential active agents are being prioritized for Phase 1 clinical trials in the COG and NANT.

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Project 9: Targeted Therapy for Neuroblastoma

Investigators at GlaxoSmithKline have developed a research consortium of laboratory investigators seeking to leverage tumor genomics information to identify therapeutic targets. Like the PPTP, we then perform comprehensive preclinical testing of pharmacologic modulators of putative targets both for proof-of-concept as well as garnering the preclinical data necessary to support clinical development. This collaboration has led to the identification of CENPE as differentially overexpressed protein in the most aggressive subset of neuroblastomas, and pharmacologic inhibitors show broad and potent cytotoxicity in vitro and in vivo (Wood, AACR 2008).

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Project 10: Translational Genomics of microRNAs in Neuroblastoma

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Selected Publications

  1. Attiyeh EF, London WB, Mossé YP, Wang Q, Winter C, Khazi D, McGrady PW, Seeger RC, Look AT, Shimada H, Brodeur GM, Cohn SL, Matthay KK, Maris JM. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med; 353:2243-53 2005. PMID: 16306521
  2. Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, Veatch J, Goldsby R, Brophy P, Kersun LS, Hawkins RA, Maris JM. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol; 25:1054-60 2007. PMID: 17369569
  3. Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, Asgharzadeh S, Attiyeh EF, Diskin SJ, Laudenslager M, Winter C, Cole KA, Glessner JT, Kim C, Frackelton EC, Casalunovo T, Eckert AW, Capasso M, Rappaport EF, McConville C, London WB, Seeger RC, Rahman N, Devoto M, Grant SF, Li H, Hakonarson H. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med; 358(24):2585-2593, 2008. PMID: 18463370 PMC2742373
  4. Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 455(7215):930-5, 2008. PMID: 18724359 PMC2672043
  5. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM. Anti-GD2 Antibody with GM-CSF, IL2 and Isotretinoin for Neuroblastoma. NEJM, 363(14): 1324-34, 2010. PMID: 20879881
  6. Cole KA, Huggins J, Laquaglia M, Hulderman CE, Russell MR, Bosse K, Diskin SJ, Attiyeh EF, Sennett R, Norris G, Laudenslager M, Wood AC, Mayes PA, Jagannathan J, Winter C, Mosse YP, Maris JM. RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A. 108:3336-3341, 2011. PMID: 21289283
  7. Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, Attiyeh EF, Mosse YP, Kim C, Diskin SJ, Cole KA, Bosse K, Diamond M, Laudenslager M, Winter C, Bradfield JP, Scott RH, Jagannathan J, Garris M, McConville C, London WB, Seeger RC, Grant SF, Li H, Rahman N, Rappaport E, Hakonarson H, Maris JM. A genome-wide association study identifies common variations in the BARD1 tumor suppressor gene predisposing to high-risk neuroblastoma. Nature Genetics 41:718-723, 2009. PMID: 19412175 PMC2753610
  8. Diskin SJ, Hou C, Glessner JT, Attiyeh EF, Laudenslager M, Bosse K, Cole K, Mossé YP, Wood A, Lynch JE, Pecor K, Diamond M, Winter C, Wang K, Kim C, Geiger EA, McGrady PW, Blakemore AI, London WB, Shaikh TH, Bradfield J, Grant SF, Li H, Devoto M, Rappaport ER, Hakonarson H, Maris JM. Copy number variation at 1q21.1 associated with neuroblastoma. Nature; 459(7249):987-991, 2009. PMID: 19536264 PMC2755253
  9. Cole KA, Huggins J, Laquaglia M, Hulderman CE, Russell MR, Bosse K, Diskin SJ, Attiyeh EF, Sennett R, Norris G, Laudenslager M, Wood AC, Mayes PA, Jagannathan J, Winter C, Mosse YP, Maris JM. An RNAi screen of the protein kinome identifies checkpoint homolog 1 (CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A. 108:3336-3341, 2011. PMID 21289283
  10. Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, Hou C, Schnepp RW, Diamond M, Bosse K, Mayes PA, Glessner J, Kim C, Frackelton E, Garris M, Wang Q, Glaberson W, Chiavacci R, Nguyen L, Jagannathan J, Saeki N, Sasaki H, Grant SF, Iolascon A, Mosse YP, Cole KA, Li H, Devoto M, McGrady PW, London WB, Capasso M, Rahman N, Hakonarson H, Maris JM. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 469:216-220, 2011. PMID 21124317

View a Comprehensive List of Publications on PubMed

A Quick Primer on Neuroblastoma


What is Neuroblastoma?

Neuroblastoma is a pediatric embryonal solid tumor of the sympathetic nervous system (SNS) that effects (600-750) number of children per year in the US. It is the most common solid tumor outside of the central nervous system (CNS) and accounts for 15% of all pediatric cancer deaths. Neuroblastoma is sometimes referred to as a "heterogeneous" disease because of the wide range in its behavior in different children-some neuroblastoma tumors go away on their own (regress), some mature into a benign growth (ganglioneuroblastoma), and some grow and spread rapidly. Since neuroblastoma arises at the interface between the nervous system and the endocrine system, it is also included in the class of neuroendocrine tumors. Neuroblastoma is not a cancer of the CNS, but occasionally neuroblastoma metastasizes to the CNS.

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Who is affected?

Neuroblastoma is a pediatric cancer. Neuroblastoma may be present at birth, but is more often diagnosed much later when the child begins to show symptoms of the disease. The presentation varies depending on the site of disease, but may include the presence of an abdominal mass, bone pain, difficulty walking, "raccoon eyes from metastatic disease to the orbits, or signs of bone marrow involvement such as pallor and easy bruising. The median age at diagnosis is about 2 years old. Neuroblastoma diagnosed after age 10 is extremely rare, but possible.

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What are the causes of Neuroblastoma?

Although the causes of mutations responsible for certain adult cancers are known (for example, cancer-causing chemicals in cigarette smoke), the reasons for DNA changes that cause neuroblastomas are not known. Many researchers think that neuroblastomas develop when normal fetal neuroblasts fail to become mature nerve cells or adrenal medull cells. Instead, they continue to grow and divide.

In rare cases (about 1% to 2%), children may inherit an increased risk of developing neuroblastoma. Children with the familial neuroblastoma come from families with one or more affected members who had neuroblastoma. Compared to children with sporadic neuroblastoma, children with familial neuroblastoma are diagnosed at an earlier age and may develop 2 or more of these cancers in different organs (for example, in both adrenal glands or in more than one sympathetic ganglion). It is important to distinguish neuroblastomas developing in several organs from neuroblastomas that have started in one organ and then spread to others (metastatic neuroblastomas).

More in "Genetic Hallmarks of Neuroblastoma" below.

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Where are the tumor sites?

The most common place for Neuroblastoma to originate is within the adrenal glands, which are located above each kidney. The tumors can also be found in the neck, chest , abdomen (30% non-adrenal), or pelvis -anywhere along the chain of the sympathetic nervous system.

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What is the frequency of occurrence of Neuroblastoma?

Neuroblastoma is a very rare cancer. Of approximately 13,000 new cases of childhood cancer in the U.S. each year, only about 650-700 are Neuroblastoma. There is similar incidence in other countries and no clear differences between ethnic groups. About 55% of all neuroblastoma patients are boys.

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How is Neuroblastoma diagnosed?

When a child comes to medical attention, and the doctor suspects s/he might have neuroblastoma, the clinician performs a variety of tests including a CT scan, a MIBG scan and test for urine catecholamines (VMA, HVA). The diagnosis of neuroblastoma is made by biopsy of the tumor or bone marrow. Based on these tests, an INSS stage and a RISK category are assigned.

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What are the different INSS stages?

Stage 1: The tumor is confined to one area of origin and can be completely removed through surgery. Although microscopic residual disease may remain after surgery, identifiable lymph nodes on both sides of the body are negative for neuroblastoma.

Stage 2A: The tumor is confined to one area but because of size, location, or proximity to other organs, cannot be completely removed. Identifiable lymph nodes on both sides of the body are negative for neuroblastoma.

Stage 2B: The tumor is confined to one area and may or may not be completely removed. Identifiable lymph nodes on the side of the body where the tumor is located are positive for neuroblastoma, but lymph nodes on the opposite side of the body are negative for neuroblastoma.

Stage 3: One of the three scenarios : 1)The tumor crosses the midline of the body (defined as the spine) and may or may not have spread to nearby lymph nodes 2) the tumor is confined to one area of the body with disease in lymph nodes on the other side of the body 3) the tumor is located crosses the midline with disease in lymph nodes on both sides of the body.

Stage 4: Neuroblastoma is found in distant lymph nodes, bone marrow, bone, liver, or other organs (except in the special circumstances of Stage 4S, explained below). Indication of presence of neuroblastoma cells by immunocytology alone (no visible tumor cells in bone marrow biopsy or aspirate) does not classify a child as stage 4.

Stage 4S: Usually in infants, the tumor is confined to one area of the body, like a Stage 1 or 2 tumor, but disease has spread to only the liver, skin, or less than 10 percent of the bone marrow (no bone lesions).

The new schema of staging is as follows:

  • L1: Localized tumor confined to one compartment of the body and absence of any Image defined risk factors (IDRFs)
  • L2: Loco-regional tumor and presence of any IDRFs
  • M: Distant metastatic disease
  • MS: Metastasis limited to skin, liver or bone marrow of children less than 18 months of age

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What are the Risk categories in patients affected with Neuroblastoma?

Patients with neuroblastoma are assigned to a "risk category" based on clinical and tumor genetic features. Neuroblastoma can be categorized currently into 3 risk groups - low, intermediate, high. The risk groups are used to determine therapy by pediatric oncologists to tailor the treatment accordingly thus enabling them to treat an individual patient the most appropriate way, avoiding treatments that are more toxic than that patient requires. For e.g. Children with low risk disease may be treated with surgery alone, whereas those with high risk disease are treated more intensely.

Risk categories

Low-risk
These patients have a good prognosis and get minimal treatment - usually surgery alone. In fact, some babies are diagnosed with neuroblastoma at birth, and have spontaneous remission - They need no anesthesia, no surgery, nothing; they are simply observed and monitored with use of x-rays and ultrasound. Over 90% of low risk patients survive.

Intermediate-risk
These patients also have a good prognosis, with moderate therapy. They are treated according to the genetic makeup of their cells, with chemotherapy and surgery. These patients also have a 90% survival rate.

High-risk
Unfortunately, these patients often have disease that is difficult to cure. Patients receive very intensive therapy, including surgery, chemotherapy, stem cell transplantation and biologic agents. Despite this, over half of the patients will suffer a relapse. Relapsed high-risk neuroblastoma is rarely cured.

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What are the factors that help in deciding the risk category?

At diagnosis, a piece of the tumor tissue is sent to a laboratory, where biological tests are run to help assign the patient to the proper risk-group and treatment protocol. Risk is decided based on the combination of the four following criteria:

  1. Age of the child
  2. Stage of the disease
  3. Tumor histology
  4. Genetic make-up of the tumor

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How is the Neuroblastoma histology determined?

The histology classifies neuroblastoma tumors further into either "Favorable" or "Unfavorable" based on tumor grade (how the cells look under the microscope) and mitosis karyorrhexis index(MKI). Assigning a tumor Grade is based on Shimada classification. The proportion of non-cancerous structural cells called "stroma" (also known as "Schwannian" cells) and the degree of differentiation of neuroblastic cells is examined and the following grades are assigned.

  • neuroblastoma (Neuroblastoma): stroma-poor, undifferentiated, poorly differentiated, or differentiating; malignant tumor
  • Gneuroblastoma i (Ganglioneuroblastoma intermixed): stroma-rich, intermixed with Neuroblasts;
  • Gneuroblastoma n (Ganglioneuroblastoma nodular): stroma-rich, nodules of neuroblasts; or
  • GN (Ganglioneuroma): stroma-dominant, benign tumor.

MKI -index gives information about cell division and activity. Dividing cells (mitosis) and cells with nuclear fragmentation (karyorrhexis) are counted and the MKI determined as follows:

  • low MKI: Less than 2% (100 cells in a sample of 5000 tumor cells);
  • intermediate MKI: 2-4% (100-200 cells per 5000 tumor cells); or
  • high MKI: 4% or more (200 or more cells per 5000 tumor cells).

Combining the above two factors together with the child's age, allow INPC classification into two groups: favorable histology (FH) and unfavorable histology (UH)

Favorable Histology
  • all ganglioneuroma (GN) and ganglioneuroblastoma intermixed (Gneuroblastomai);
  • ganglioneuroblastoma nodular (Gneuroblastoman) with 50% or more Schwannian cells;
  • neuroblastoma (neuroblastoma), under 18 months; or
  • neuroblastoma (neuroblastoma), under 5 years old, differentiating, low MKI.
Unfavorable Histology
  • ganglioneuroblastoma nodular (Gneuroblastoman) with less than 50% Schwannian cells;
  • neuroblastoma (neuroblastoma), undifferentiated;
  • neuroblastoma (neuroblastoma), high MKI;
  • neuroblastoma (neuroblastoma), poorly differentiated or differentiating, intermediate MKI, over 18 months; or
  • neuroblastoma (neuroblastoma), differentiating, low MKI, over 5 years old.

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What are the key genetic hallmarks of Neuroblastoma?

Ploidy. DNA diploidy although normal in healthy cell, is a poor prognostic factor for neuroblastoma and indicates higher risk disease. Triploidy or hyperdiploidy in a neuroblastoma cell is favorable.

MYCN. Another genetic factor considered in risk assignment is MYCN amplification status . MYCN is an oncogene and is an unfavorable prognostic factor. When there are more than 10 copies present in a cell, the neuroblastoma tumor is referred to as MYCN amplified. MYCN is commonly multiplied, by 100 times, and has been found as high as 700 times in a neuroblastoma cell. About 20% of all neuroblastoma cases have MYCN amplification. It is more common in widespread disease than localized tumors. MYCN amplification is found in less than 10% of stage 1 & 2 cases, in about 10% of stage 4s, and in about 30% of stage 3 & 4 cases . MYCN is an important prognostic factor. Younger children and children with lower stage disease will be treated as high-risk if their tumor is MYCN amplified, but MYCN does not necessarily contribute to a poorer prognosis in high-risk cases because one or more unfavorable characteristics are present in all high-risk cases.

Other genetic and molecular factors. Other genetic variables believed to have prognostic value for Neuroblastoma have been identified, but not all are currently used in risk assignment.

  • 1p & 3p chromosomes: Tumor suppressor genes are believed to be associated with 1p and 3p chromosomes, and deletion of either in the neuroblastoma is considered an unfavorable prognostic factor.
  • 11q chromosome: 11q deletions may also predict a less favorable prognosis. It is thought that these chromosome parts -- missing in many neuroblastoma patients -- may contain important Tumor Suppressor Genes
  • 17q Chromosome: Having an extra part of chromosome 17 or 17 q gain is also linked with a worse prognosis; this probably means that there is an oncogene in this part of chromosome 17. Understanding the importance of chromosome deletions/gains is an active area of neuroblastoma research.
  • TRKA & CD44: A tumor suppressor gene called TrkA is sometimes less active than usual in neuroblastoma cells, which may be another reason for uncontrolled growth. A lack of TRKA and CD44 expression on the neuroblastoma cell surface are also considered unfavorable, but not independently prognostic.
  • Neurotrophin receptors: Neuroblastomas with more neurotrophin receptors, especially the nerve growth factor receptor called TrkA, may have a more favorable prognosis.
  • Ferritin, NSE & GD2: These serum markers are released by Neuroblastoma cells into the blood. Patients with high ferritin levels tend to have a worse prognosis. Neuron-specific enolase Increased levels of NSE (Neuron Specific Enolase) and LDH(Lactose Dehydrogenase) in the blood predict a worse outlook for children with neuroblastoma. A substance on the surface of many nerve cells known as ganglioside GD2 is often increased in the blood of neuroblastoma patients. Although the usefulness of GD2 in predicting prognosis is unknown, it may turn out to be more useful in treating neuroblastoma.
  • ALK: Recent research suggests that inherited mutations in the ALK gene may account for most cases of hereditary neuroblastoma.

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What are the different treatment options?

Surgery. This is common in neuroblastoma treatment and serves to take out as much of the cancer as possible. If necessary, surgery is delayed until chemotherapy and/or radiation has decreased tumor size.

Radiation therapy. Both high dose X-rays (external beam) and radioisotopes through thin plastic tubes, (internal radiation) therapies may be used.

Chemotherapy. Common chemotherapy agents are: daunorubicin, cyclophosphamide, carboplatin, and epotoside.

Bone marrow transplantation. Autologous BMT may be used following aggressive chemotherapy.

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