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PCGP Researchers Find Gene Tied To Neuroblastoma Age-at-Diagnosis

NEW YORK (GenomeWeb News) – Recurrent mutations in a gene called ATRX correspond to neuroblastoma age-at-diagnosis, according to a study in today's issue of the Journal of the American Medical Association.

Members of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project did genome sequencing on matched tumor-normal samples from 40 individuals with metastatic neuroblastoma who had been diagnosed with the disease as infants, children, or adolescents/young adults.

A quarter of the tumor genomes contained mutations or structural changes to ATRX, a gene involved in telomere maintenance, chromatin remodeling, and nucleosome assembly. But these mutations were more common in individuals diagnosed as adolescents/young adults or in diagnostic tumors from children with chronic disease progression and did not turn up in tumor sample from infants — a pattern that held when researchers looked for ATRX mutations in dozens more neuroblastoma samples. Alterations in the gene also corresponded to longer telomeres in tumors.

The findings are intriguing, since older age-at-diagnosis corresponds to worse neuroblastoma outcomes and somewhat different disease progression, hinting that ATRX mutations may define a distinct subset of neuroblastoma.

"This suggests we may need to think about different treatment strategies for patients depending on whether or not they have the ATRX mutation," co-author Richard Wilson, director of Washington University's Genome Institute, said in a statement.

It has been known for some time that disease progression patterns and outcomes vary in neuroblastoma depending when individuals are diagnosed with the disease, study authors noted. "[W]ith current treatment approaches, the age at diagnosis has proven to be one of the most powerful predictors of outcome."

While the overall survival rate for infants diagnosed with neuroblastoma is around 88 percent, for instance, the survival rate drops to 49 percent for children diagnosed between the ages of 18 months and 11 years old.

For those diagnosed as adolescents and young adults, the overall survival rate is even worse at around 10 percent, though short-term survival rate tends to be higher. That's because those diagnosed with neuroblastoma when they are 12 or older are more prone to chronic or "indolent" neuroblastoma, researchers explained, which can lead to death after many years of disease.

To get a better sense of the genetic features behind neuroblastoma, the PCGP used paired-end Illumina sequencing to sequence matched germline and diagnostic neuroblastoma tumor genomes using samples collected at Memorial Sloan-Kettering Cancer Center over more than two decades.

The samples came from 40 patients with stage 4, metastatic neuroblastoma, including six infants younger than 18 months old, 29 children under 12 years old, and five adolescent/young adults aged 12 or older. Study authors noted that around half of individuals with neuroblastoma have advanced, metastatic disease at the time they are diagnosed.

In the tumor genomes of all five individuals diagnosed with neuroblastoma as adolescents or young adults, researchers found mutations or structural variations ATRX.

In contrast, alterations in the ATRX gene were less common in neuroblastoma tumors from those diagnosed as children. Tumors from five of the 29 children tested had ATRX changes, while none of the infants' diagnostic tumors contained detectable mutations in the gene.

When they screened for ATRX changes in tumor samples from another 64 infants, children, or adolescents and young adults, the investigators again found that mutations in the gene were more common in the adolescent/young adult group and in children with disease patterns resembling those seen in chronic neuroblastoma.

Across all 104 tumors tested by genome sequencing or targeted ATRX testing, the team saw mutations in the gene in 44 percent of tumors from individuals diagnosed as adolescents/young adults, in 17 percent of children's tumors, and in none of the infant tumors.

"The mutation we found is associated with patients in the older age group, but it also identifies for the first time a subset of younger patients who turned out to have an indolent form of neuroblastoma," corresponding author Michael Dyer, a developmental neurobiology researcher at St. Jude, said in a statement.

If so, the researchers explained, the presence or absence of ATRX alterations may eventually help in predicting disease progression and guiding treatment in newly diagnosed neuroblastoma patients. Still, they cautioned that more work is needed to assess the consequences of ATRX mutations in neuroblastoma across an even broader age range.

St. Jude researchers are reportedly screening for compounds that are active against ATRX mutation-containing neuroblastoma cells, focusing on drugs that have already been approved for use in the US.