William L Hwang1,2, Rachel L Wolfson2, Andrzej Niemierko2,3, Karen J Marcus2,4,5, Steven G DuBois2,6, Daphne Haas-Kogan2,4,5. 1. Harvard Radiation Oncology Program, Boston, MA. 2. Harvard Medical School, Boston, MA. 3. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA. 4. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA. 5. Department of Radiation Oncology, Brigham & Women's Hospital, Boston, MA. 6. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Abstract
BACKGROUND: Neuroblastoma is the most common pediatric extracranial solid tumor. Within conventional risk groups, there is considerable heterogeneity in outcomes, indicating the need for improved risk stratification. METHODS: In this study we analyzed the somatic mutational burden of 515 primary, untreated neuroblastoma tumors from three independent cohorts. Mutations in coding regions were determined by whole-exome/genome sequencing of tumor samples compared to matched blood leukocytes. Survival data for 459 patients were available for analysis of 5-year overall survival using the Kaplan-Meier method and log-rank test. All statistical tests were two-sided. RESULTS: Despite a low overall somatic mutational burden (mean = 3, range = 0-56), 107 patients were considered to have high mutational burden (>3 mutations). Unfavorable histology and age 18 months and older were associated with high mutational burden. Patients with high mutational burden had inferior 5-year overall survival (29.0%, 95% confidence interval [CI] = 17.2 to 41.8%) vs those with three or fewer somatic mutations (76.2%, 95% CI = 71.5 to 80.3%) (log-rank P < .001) and this association persisted when limiting the analysis to genes included on a 447-gene panel commonly used in clinical practice. On multivariable analysis, mutational burden remained prognostic independent of age, stage, histology and MYCN status. CONCLUSIONS: This study demonstrates that mutational burden of primary neuroblastoma may be useful in combination with conventional risk factors to optimize risk stratification and guide treatment decisions, pending prospective validation.
BACKGROUND:Neuroblastoma is the most common pediatric extracranial solid tumor. Within conventional risk groups, there is considerable heterogeneity in outcomes, indicating the need for improved risk stratification. METHODS: In this study we analyzed the somatic mutational burden of 515 primary, untreated neuroblastoma tumors from three independent cohorts. Mutations in coding regions were determined by whole-exome/genome sequencing of tumor samples compared to matched blood leukocytes. Survival data for 459 patients were available for analysis of 5-year overall survival using the Kaplan-Meier method and log-rank test. All statistical tests were two-sided. RESULTS: Despite a low overall somatic mutational burden (mean = 3, range = 0-56), 107 patients were considered to have high mutational burden (>3 mutations). Unfavorable histology and age 18 months and older were associated with high mutational burden. Patients with high mutational burden had inferior 5-year overall survival (29.0%, 95% confidence interval [CI] = 17.2 to 41.8%) vs those with three or fewer somatic mutations (76.2%, 95% CI = 71.5 to 80.3%) (log-rank P < .001) and this association persisted when limiting the analysis to genes included on a 447-gene panel commonly used in clinical practice. On multivariable analysis, mutational burden remained prognostic independent of age, stage, histology and MYCN status. CONCLUSIONS: This study demonstrates that mutational burden of primary neuroblastoma may be useful in combination with conventional risk factors to optimize risk stratification and guide treatment decisions, pending prospective validation.
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