JAMA：ATRX遗传突变与儿童神经母细胞瘤诊断时年龄之间有相关性

Association of Age at Diagnosis and Genetic Mutations in Patients With Neuroblastoma

Nai-Kong V. Cheung, MD, PhD; Jinghui Zhang, PhD; Charles Lu, PhD; Matthew Parker, PhD; Armita Bahrami, MD; Satish K. Tickoo, MD; Adriana Heguy, PhD; Alberto S. Pappo, MD; Sara Federico, MD; James Dalton, BS; Irene Y. Cheung, ScD; Li Ding, PhD; Robert Fulton, MS; Jianmin Wang, PhD; Xiang Chen, PhD; Jared Becksfort, MS; Jianrong Wu, PhD; Catherine A. Billups, MS; David Ellison, MD, PhD; Elaine R. Mardis, PhD; Richard K. Wilson, PhD; James R. Downing, MD; Michael A. Dyer, PhD for the St Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

Context Neuroblastoma is diagnosed over a wide age range from birth through young adulthood, and older age at diagnosis is associated with a decline in survivability.

Objective To identify genetic mutations that are associated with age at diagnosis in patients with metastatic neuroblastoma.

Design, Setting, and Patients Whole genome sequencing was performed on DNA from diagnostic tumors and their matched germlines 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). To confirm the findings from this discovery cohort, validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 also was performed. Formalin-fixed, paraffin-embedded tumor tissue was used for immunohistochemistry and fluorescence in situ hybridization. Telomere lengths were analyzed using whole genome sequencing data, quantitative polymerase chain reaction, and fluorescent in situ hybridization.

Main Outcome Measure Somatic recurrent mutations in tumors from patients with neuroblastoma correlated with the age at diagnosis and telomere length. Results In the discovery cohort (n = 40), mutations in the ATRX gene were identified in 100% (95% CI, 50%-100%) of tumors from patients in the adolescent and young adult group (5 of 5), in 17% (95% CI, 7%-36%) of tumors from children (5 of 29), and 0% (95% CI, 0%-40%) of tumors from infants (0 of 6). In the validation cohort (n = 64), mutations in the ATRX gene were identified in 33% (95% CI, 17%-54%) of tumors from patients in the adolescent and young adult group (9 of 27), in 16% (95% CI, 6%-35%) of tumors from children (4 of 25), and in 0% (95% CI, 0%-24%) of tumors from infants (0 of 12). In both cohorts (N = 104), mutations in the ATRX gene were identified in 44% (95% CI, 28%-62%) of tumors from patients in the adolescent and young adult group (14 of 32), in 17% (95% CI, 9%-29%) of tumors from children (9 of 54), and in 0% (95% CI, 0%-17%) of tumors from infants (0 of 18). ATRX mutations were associated with an absence of the ATRX protein in the nucleus and with long telomeres.

Conclusion ATRX mutations were associated with age at diagnosis in children and young adults with stage 4 neuroblastoma.