From Medscape Medical News > Oncology

Neuroblastoma Genetics Tell Tale of 2 Tumor Types

Neil Osterweil

March 13, 2012 — A genetic analysis of neuroblastoma samples from children and young adults suggests that tumors originating in adolescents have a high frequency of a specific mutation that is absent in neuroblastoma in infants.
This finding points to a potential molecular marker for chronic but progressive neuroblastoma, and hints at possible therapeutic targets or personalized treatment strategies, write Nai-Kong V. Cheung, MD, PhD, and colleagues from the Pediatric Cancer Genome Project — a joint effort by researchers from the St. Jude's Children's Research Hospital in Memphis, Tennessee, and from Washington University in St. Louis, Missouri — in their report published in the March 14 issue of JAMA: The Journal of the American Medical Association.
Mutations in ATRX, a gene associated with the alpha-thalassemia/mental retardation X-linked syndrome, appear to be independent of amplifications in the MYCN gene, which are associated with poor-prognosis neuroblastomas, coinvestigator Alberto Pappo, MD, director of the solid tumor division at St. Jude's, told Medscape Medical News.
"The presence of ATRX appears to identify a subset of patients with neuroblastoma who are older than 5 years of age and lack MYCN amplification. More studies are needed to define the prognostic significance of this finding, as well as possible therapeutic avenues," he noted.
Important Implications
"It's a very significant finding, in that the presence of these mutations, if confirmed in larger studies, can delineate or identify the subgroup of patients in the older age range who might be rerouted to receive another type of therapy," said Rani E. George, MD, PhD, a pediatric solid tumor oncologist at the Dana-Farber Cancer Institute, and assistant professor of pediatrics at Harvard Medical School, both in Boston, Massachusetts, who was not involved in the study.
Age at diagnosis of neuroblastoma is a strong predictor of outcome, the investigators note, with overall survival probabilities ranging from 88% in infancy, to 49% in toddlers and preteens, to 10% in adolescents and young adults.
"A majority of neuroblastomas occurring in adolescents and young adults, as well as in some older children, have a protracted course, with death occurring many years after diagnosis," they write.
The investigators performed whole-genome sequencing on DNA from tumor samples from 40 patients with metastatic melanoma, along with their matched tumor germ-lines. They labeled this group the discovery cohort. They also tested tumor samples from 64 patients diagnosed from 1985 to 2009 (the validation cohort).
In samples from the discovery cohort, the investigators identified ATRX mutations in 0 of 6 samples (0%) from infants younger than 18 months, in 5 of 29 samples (17%) from children between 18 months and 12 years, and in 5 of 5 samples (100%) from those 12 years and older.
Similarly, ATRX mutations were found in 9 of 27 samples (33%) from adolescents/young adults, in 4 of 25 samples (16%) from children 18 months to 12 years, and in 0 of 12 samples (0%) from infants.
The mutations appeared to be associated with an absence of the ATRX protein in the nucleus, and with long telomeres, although the investigators could not explain how a loss-of-function mutation results in longer telomeres.
Possible Markers
Medscape Medical News asked senior investigator Michael Dyer, PhD, from St. Jude's, whether ATRX mutations are markers for disease severity, which increase in frequency as the child ages and the disease progresses.
"Our study did not specifically explore the mutation spectrum across different stages of disease within a single age group," he replied. "Given the other factors associated with survival in neuroblastoma, this would require a large multivariate analysis. We are working to establish a collaboration to address this question directly."
"However," he continued, "if our findings are only applicable to the most advanced stages of neuroblastoma, that does not diminish their significance. Indeed, the stage 4 patients are particularly important from a clinical and translational perspective, as they have the worst outcome."
Dr. George noted that the identification of patients with the mutations will enable clinicians to tailor therapy to individual patients. "Possibly a less toxic chemotherapy can be given or, as more is known about the ATRX gene and what is does, therapy can be personalized to patients who have these mutations," she said.
The study was supported by grants from the National Cancer Institute at the National Institutes of Health, the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, the Catie Hoch Foundation, and the Robert Steel Foundation. Dr. Cheung reports holding patents for monoclonal antibodies, beta-glucan, GD2 peptide mimetics, and methods for detecting residual disease; and receiving royalties from United Therapeutics and Biotec Pharmacon. Dr. Pappo reports serving as a consultant to Ziopharm. The remaining coauthors and Dr. George have disclosed no relevant financial relationships.
JAMA. 2012;307:1062-1071. Abstract