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

Cheung NV, Zhang J, Lu C, et al. — Wed, 14 Mar 2012 00:00:00 GMT

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

Mortality in Adults With Sickle Cell Disease and Pulmonary Hypertension

Mehari A, Gladwin MT, Tian X, et al. — Wed, 28 Mar 2012 00:00:00 GMT

To the Editor: Noninvasive echocardiographic markers of elevated pulmonary artery pressure have been associated with early mortality in some studies in adults with sickle cell disease (SCD), but considerable controversy remains regarding the prevalence of pulmonary hypertension and its contribution to mortality. We assessed prevalence and survival in a cohort of patients with SCD with pulmonary hypertension documented by right heart catheterization (RHC).

JAMA: Sickle Cell Disease/Thalassemias Topic Collection

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

Mortality in Adults With Sickle Cell Disease and Pulmonary Hypertension