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

Purpose: To improve risk prediction in neuroblastoma and to specify the type of a possible relapse, alterations in the long arm of chromosome 11 were 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 611 tumors 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). Event-free 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, the 11q status did not discriminate outcome. By multivariate analysis, the 11q 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.

[1]  F. Berthold,et al.  Risk estimation in localized unresectable single copy MYCN neuroblastoma by the status of chromosomes 1p and 11q. , 2006, Cancer letters.

[2]  E. Connolly,et al.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. , 2006, Neurosurgery.

[3]  Frank Speleman,et al.  Positional and functional mapping of a neuroblastoma differentiation gene on chromosome 11 , 2005, BMC Genomics.

[4]  K. Leibundgut,et al.  Characterization of karyotypic events and evolution in neuroblastoma , 2005, Pediatric blood & cancer.

[5]  F. Berthold,et al.  MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. , 2004, European journal of cancer.

[6]  D Catchpoole,et al.  Oligonucleotide microarray analysis of gene expression in neuroblastoma displaying loss of chromosome 11q. , 2004, Carcinogenesis.

[7]  B. Weber,et al.  Identification and high-resolution mapping of a constitutional 11q deletion in an infant with multifocal neuroblastoma. , 2003, The Lancet. Oncology.

[8]  I. Bar-Am,et al.  der(11)t(11;17): a distinct cytogenetic pathway of advanced stage neuroblastoma (NBL) - detected by spectral karyotyping (SKY). , 2003, Cancer letters.

[9]  F. Berthold,et al.  Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  F. Westermann,et al.  Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations , 2002, Genes, chromosomes & cancer.

[11]  P. Ambros,et al.  Pathology and biology guidelines for resectable and unresectable neuroblastic tumors and bone marrow examination guidelines. , 2001, Medical and pediatric oncology.

[12]  B. Morland,et al.  Molecular cytogenetic characterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17). , 2001, Cancer genetics and cytogenetics.

[13]  J. Mann,et al.  Neuroblastomas with chromosome 11q loss and single copy MYCN comprise a biologically distinct group of tumours with adverse prognosis , 2001, British Journal of Cancer.

[14]  F. Speleman,et al.  Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification , 2001, International journal of cancer.

[15]  D. Stram,et al.  Comprehensive analysis of chromosome 1p deletions in neuroblastoma. , 2001, Medical and pediatric oncology.

[16]  D. Stram,et al.  Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma. , 2001, Medical and pediatric oncology.

[17]  R. Stallings,et al.  Coordinate deletion of chromosome 3p and 11q in neuroblastoma detected by comparative genomic hybridization. , 2000, Cancer genetics and cytogenetics.

[18]  D. Stram,et al.  Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas , 1999, Oncogene.

[19]  F. Speleman,et al.  Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization , 1998, Genes, chromosomes & cancer.

[20]  I. Lewis,et al.  Promiscuous translocations of chromosome arm 17q in human neuroblastomas , 1997, Genes, chromosomes & cancer.

[21]  J. Maris,et al.  Biology and genetics of human neuroblastomas. , 1997, Journal of pediatric hematology/oncology.

[22]  D. Le Paslier,et al.  Additional copies of a 25 Mb chromosomal region originating from 17q23.1‐17qter are present in 90% of high‐grade neuroblastomas , 1996, Genes, chromosomes & cancer.

[23]  A. Vianna-Morgante,et al.  Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q. , 1995, American journal of medical genetics.

[24]  F. Berthold,et al.  Revisions of the international criteria for neuroblastoma diagnosis, staging and response to treatment. , 1993, Progress in clinical and biological research.

[25]  H. Varmus,et al.  Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. , 1984, Science.

[26]  J. Trent,et al.  Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour , 1983, Nature.