Frequency and Prognostic Significance of Genetic Abnormalities in a Subgroup of Patients With Intermediate-Risk
Hannah E Hartley1,2, Fang Chyi Fong1,3, Alem S Gabriel1
1Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Purpose:
Intermediate-risk neuroblastoma patients older than 18 months, with non-MYCN amplified, International Neuroblastoma Risk Group Staging System localized, unresectable or International Neuroblastoma Staging System stage 3 tumors, and unfavorable histology have inferior outcomes compared with other intermediate-risk patients. This study aimed to identify genetic prognostic biomarkers within this rare subgroup.
Methods:
We conducted a large, international study including chromosomal copy number in all cases, next-generation DNA sequencing in most, and telomere maintenance mechanisms and gene expression in a subset, and correlated results with patient survival.
Results:
Among 98 tumors, 9/98 (9.2%) had oncogene amplifications (CDK4/MDM2/TERT coamplification (n = 1), CDK4/MDM2 coamplification (n = 4), CDK4 (n = 2), TERT (n = 1), and MYC (n = 1)), while 63/98 (64.3%) had typical segmental chromosomal aberrations (tSCAs). Patients with tumors with oncogene amplification had the worst 5-year event-free survival (EFS; 0%; P < .0001 log-rank test) and 5-year overall survival (OS; 44.4% [95% CI, 21.4 to 92.3]; P < .01 log-rank test). Patients with tumors harboring tSCAs had inferior EFS compared with those with numerical chromosomal aberrations only (51.7% [95% CI, 40.6 to 65.8] v 93.3% [95% CI, 81.5 to 100]; P < .01). Patients with p53 pathway tumor alterations (n = 10) had worse EFS than those without (0% v 61.1% [95% CI, 50.3 to 74.3]; P < .0001, log-rank test) and worse OS (26.7% [95% CI, 8.9 to 80.3] v 80.9% [95% CI, 71.8 to 91.3]; P < .001 log-rank test). Multivariable analysis identified tSCAs as an independent prognostic variable for EFS and oncogene amplification or p53 pathway abnormalities as independent prognostic variables for EFS and OS.
Conclusion:
Oncogene amplification and/or p53 pathway abnormalities and/or typical SCAs identify patients with intermediate-risk neuroblastoma with inferior outcome for whom intensified or alternative treatments should be considered.