Association of age at diagnosis and genetic mutations in patients with neuroblastoma Journal Article
| Authors: | Cheung, N. K. V.; Zhang, J.; Lu, C.; Parker, M.; Bahrami, A.; Tickoo, S. K.; Heguy, A.; Pappo, A. S.; Federico, S.; Dalton, J.; Cheung, I. Y.; Ding, L.; Fulton, R.; Wang, J.; Chen, X.; Becksfort, J.; Wu, J.; Billups, C. A.; Ellison, D.; Mardis, E. R.; Wilson, R. K.; Downing, J. R.; Dyer, M. A. |
| Article Title: | Association of age at diagnosis and genetic mutations in patients with neuroblastoma |
| Abstract: | 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. ©2012 American Medical Association. All rights reserved. |
| Keywords: | immunohistochemistry; adolescent; adult; child; controlled study; human tissue; preschool child; school child; child, preschool; young adult; unclassified drug; oncoprotein; gene mutation; somatic mutation; frameshift mutation; gene deletion; genetics; missense mutation; mutation; clinical trial; advanced cancer; validation process; cancer staging; polymerase chain reaction; protein function; protein localization; telomere; in situ hybridization, fluorescence; disease association; metastasis; cohort studies; nuclear protein; cohort analysis; genetic association; genetic variability; gene function; pathology; mutational analysis; age; nuclear proteins; oncogene; fluorescence in situ hybridization; infant; infant, newborn; neuroblastoma; quantitative analysis; nucleotide sequence; newborn; neoplasm metastasis; dna sequence; dna mutational analysis; helicase; onset age; age of onset; chromosome analysis; nonsense mutation; dna helicases; genetic identification; sequence analysis, dna; protein atrx; atrx protein, human; atrx gene; telomere homeostasis |
| Journal Title: | JAMA - Journal of the American Medical Association |
| Volume: | 307 |
| Issue: | 10 |
| ISSN: | 0098-7484 |
| Publisher: | American Medical Association |
| Date Published: | 2012-03-14 |
| Start Page: | 1062 |
| End Page: | 1071 |
| Language: | English |
| DOI: | 10.1001/jama.2012.228 |
| PROVIDER: | scopus |
| PUBMED: | 22416102 |
| PMCID: | PMC3527076 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 April 2012" - "CODEN: JAMAA" - "Source: Scopus" |
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