(ChemotherapyAdvisor) – Children, adolescents, and young adults with metastatic neuroblastoma — but not those younger than 5 years of age at diagnosis — have ATRX mutations present in tumors, a study in the March 14 issue of JAMA has found.

This identification of the first genetic mutation associated with neuroblastoma provides a clue to the long-recognized but poorly understood link between treatment outcome and age at diagnosis: Probability of overall survival is 88% in infants, 49% in children, and 10% in adolescents or young adults.

The investigators performed whole-genome sequencing on DNA from diagnostic stage 4 tumors and their matched germline samples obtained between 1987 and 2009 from 40 patients. Age at diagnosis was grouped into infants (0 to <18 months; n=6), children (18 months to <12 years; n=29) and adolescents and young adults (≥12 years; n=5). Validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 was also performed; this group included 12 infants, 25 children, and 27 adolescents and young adults.

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In the study cohort, ATRX gene mutations were identified in 100% of tumors from patients in the adolescent and young adult group, 17% of tumors from children, and 0% of tumors from infants; in the validation cohort, these percentages were 33%, 16%, and 0%, respectively. ATRX mutations were found to be associated with an absence of the ATRX protein in the nucleus and with long telomeres.

In both cohorts, mutations in the ATRX gene were identified in 44% of tumors from patients in the adolescent and young adult group, in 17% of tumors from children — but only in those ages 5 years and older — and in 0% of tumors from infants.

“These results suggest that inactivation of the ATRX pathway correlates with older age at diagnosis and may provide a molecular marker and potential therapeutic target for neuroblastoma among adolescents and young adults,” the researchers wrote.

Future studies of larger international cohorts will help determine short- and long-term outcomes for patients with neuroblastoma across all age groups in those with and without ATRX mutations. “These data may be useful in defining a more relevant age cut-off for the adolescent and young adult group and help to identify more effectively those patients who will have an increased risk of developing chronic or indolent neuroblastoma,” they concluded.


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