Study finds association between genetic mutation and age at diagnosis for common childhood cancer
Certain mutations of the gene ATRX were associated with age at diagnosis in children and young adults with advanced-stage neuroblastoma, a cancer that grows in parts of the nervous system, according to a study in the March 14 issue of JAMA.
Neuroblastoma is the most common extracranial (outside the cranium) solid tumor of childhood and accounts for 15 percent of all cancer-related deaths in children. "Half of the patients (50 percent) with neuroblastoma present with metastatic disease; with current treatment approaches, the age at diagnosis has proven to be one of the most powerful predictors of outcome. The probability of overall survival is 88 percent in infants [age: less than 18 months at time of diagnosis], 49 percent in children [age: 18 months less than 12 years], and only 10 percent in adolescents or young adults [age: 12 years or older]," according to background information in the article. "Genetic mutations associated with neuroblastoma and its clinical course are not completely understood."
Nai-Kong V. Cheung, M.D., Ph.D., of the Memorial Sloan-Kettering Cancer Center, New York, and colleagues conducted a study to identify genetic mutations that are associated with age at diagnosis in patients with metastatic neuroblastoma. Whole genome sequencing was performed of DNA from diagnostic tumors and their matched germlines (those cells of an individual that have genetic material that could be passed to offspring) from 40 patients with metastatic neuroblastoma obtained between 1987 and 2009. Age groups at diagnosis included infants (0-<18 months), children (18 months-<12 years), and adolescents and young adults (12 years or older). To confirm the findings from this cohort (the discovery cohort), validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 also was performed.
The researchers found that all 5 samples from adolescents and young adult patients in the discovery cohort had ATRX mutations (100 percent), whereas no ATRX mutations were detected in 6 samples obtained from infants (0 percent); among the 29 children ages 18 months to 12 years, ATRX mutations were identified in 5 (17 percent), with 4 of 5 patients living at least twice as long as their time to first relapse. A significant association was observed for the discovery cohort between ATRX mutation and age group.
"In the validation cohort (n = 64), mutations in the ATRX gene were identified in 33 percent of tumors from patients in the adolescent and young adult group (9 of 27), in 16 percent of tumors from children (4 of 25), and in 0 percent of tumors from infants (0 of 12). In both cohorts (n = 104), mutations in the ATRX gene were identified in 44 percent of tumors from patients in the adolescent and young adult group (14 of 32), in 17 percent of tumors from children (9 of 54), and in 0 percent of tumors from infants (0 of 18)," the authors write. Analysis of the data indicated a significant association between ATRX mutation and age of disease diagnosis.
"These results suggest that inactivation [disruption] 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 write.
The authors add that future studies should focus on assembling larger international cohorts of patients to study the short-term and long-term outcomes for patients with neuroblastoma across all age groups with ATRX mutations compared with those without ATRX mutations. "These data may be useful in defining a more relevant age cutoff 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 [protracted] neuroblastoma."
More information: JAMA. 2012;307:1062-1071.
Provided by JAMA and Archives Journals
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