TY - JOUR
T1 - Association of age at diagnosis and genetic mutations in patients with neuroblastoma
AU - Cheung, Nai Kong V.
AU - Zhang, Jinghui
AU - Lu, Charles
AU - Parker, Matthew
AU - Bahrami, Armita
AU - Tickoo, Satish K.
AU - Heguy, Adriana
AU - Pappo, Alberto S.
AU - Federico, Sara
AU - Dalton, James
AU - Cheung, Irene Y.
AU - Ding, Li
AU - Fulton, Robert
AU - Wang, Jianmin
AU - Chen, Xiang
AU - Becksfort, Jared
AU - Wu, Jianrong
AU - Billups, Catherine A.
AU - Ellison, David
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Downing, James R.
AU - Dyer, Michael A.
PY - 2012/3/14
Y1 - 2012/3/14
N2 - 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. Trial Registration clinicaltrials.gov Identifier: NCT00588068.
AB - 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. Trial Registration clinicaltrials.gov Identifier: NCT00588068.
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U2 - 10.1001/jama.2012.228
DO - 10.1001/jama.2012.228
M3 - Article
C2 - 22416102
AN - SCOPUS:84858248558
SN - 0098-7484
VL - 307
SP - 1062
EP - 1071
JO - JAMA
JF - JAMA
IS - 10
ER -