Frequency and Prognostic Significance of Genetic Abnormalities in a Subgroup of Patients With Intermediate-Risk Neuroblastoma: A SIOPEN Study.
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Hartley Hannah E, Fong Fang Chyi, Gabriel Alem S, Stevenson Louise K, Beckett Emily, Allinson Lisa M, Goodman Angharad, Potts Aaron, Whittle Emily, Barford Ruby, Lamparelli Alice, Herd Fiona, Mazzocco Katia, Pezzolo Annalisa, Morini Martina, Ardito Martina, Eva Alessandra, Ognibene Marzia, Fischer Matthias, Ackermann Sandra, Rosswog Carolina, Hero Barbara, Smith Graham R, Unsworth Adrienne A, McCorkindale Michael, George Sally L, Tall Jennifer, Molenaar Jan J, Matser Yvette, Langenberg Karin, Tytgat Godelieve, Noguera Rosa, Berbegall Ana P, de Mora Jaime Font, Combaret Valérie, Pierron Gaelle, Mühlethaler-Mottet Annick, Schoumans Jacqueline, Tchinda Joëlle, Banzola Irina, Jeison Marta, Hameiri-Grossman Michal, Beiske Klaus H, Auger Nathalie, Van Roy Nadine, Basta Nermine O, McNally Richard J Q, Taschner-Mandl Sabine, Papadakis Vassilios, Di Cataldo Andrea, Wheeler Kate, Bermúdez Jose D, Beck-Popovic Maja, Segura Vanessa, Canete Adela, Schleiermacher Gudrun, Tweddle Deborah A
Аннотация
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.