Loss in Chromosome 11q Identifies Tumors with Increased Risk for Metastatic Relapses in Localized and 4S Neuroblastoma

Abstract

Purpose: To improve risk prediction in neuroblastoma and to specify the type of a possible relapse, alterations in the long arm of chromosome 11were analyzed. Experimental Design: A representative cohort of 611 neuroblastomas was investigated for deletion events in distal chromosome 11q using interphase fluorescence in situ hybridization. Results: Alterations in 11q were found in 159 of 611tumors in the whole cohort (26%) and were associated with stage 4 disease (P < 0.001) and age at diagnosis of >2.5 years (P < 0.001). Eventfree survival and overall survival were significantly poorer for patients with 11q loss in the whole cohort (event-free survival and overall survival, P < 0.001) and in different subsets: neuroblastoma without MYCN amplification (MNA) (event-free survival and overall survival, P < 0.001), with MNA (event-free survival, P = 0.03; overall survival, P = 0.02), and MYCN-nonamplified stage 1, 2, 3, and 4S tumors with and without del 1p (event-free survival and overall survival, P < 0.001). In stage 4, the11q status did not discriminate outcome. By multivariate analysis, the11q status proved prognostic for event-free survival in the whole cohort (P = 0.008; hazard ratio, 1.573) and in the subgroup of stages 1, 2, 3, and 4S without MNA (P < 0.001; hazard ratio, 3.534). Moreover, 11q alterations were strongly correlated with the occurrence of metastatic relapses (P < 0.001). Conclusion:In addition to the current risk stratification, the status of 11q enables the identification of patients with an increased risk for relapses in general and metastatic relapses in particular.

Age‐dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma

“…G1 tumors showed an average of 10.5 CNAs (range, 0-18) with 9.6 (range, 0-16) numerical and 0.7 (range, 0-8) segmental aberrations. G2 showed a mean of 10.8 (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], including 7.2 (range, 0-16) numerical and 3.6 (range, 0-10) segmental changes. Finally, the CNA mean in G3 was 10.6 (range, 1-19): 3.6 (range, 0-15) numerical and 7.0 (range, 1-15) segmental CNAs.…”

“…Loss of chromosomes 1p, 3p, 9p and 11q and gain of 1q, 2p and 17q were commonly observed in patients with disseminated disease and unfavorable outcome. [8][9][10][11][12][13] Abnormal gene expression profiles were also found associated with disease aggressiveness and tumor progression. [14][15][16][17][18][19] The foregoing indicates that tumor aggressiveness of metastatic NB depends on patients' age, genomic alterations and transcriptome deregulation.…”

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

“…Outcome of 4S tumours is similar to Stages 1 and 2 unless other unfavourable prognostic markers are present. 3 Beside tumour stage, many clinical and genetic features are utilized in NB to modulate appropriate treatment and accurately define prognosis. Age >18 months 4 and histology 5 are potent indicators of poorer outcome.…”

Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

“…Существует также обратная корреляция между нали-чием в опухоли делеции 11q и амплификацией гена MYCN [16]. Американские исследователи выдвинули предложение считать потерю локуса 11q23 полезным прогностическим маркером в случаях, связанных с низ-ким (I, II или IVS стадии) или средним (благоприятная III стадия или младенцы с IV стадией без амплифика-ции гена MYCN) риском течения нейробластомы [27,29,50].…”