An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961

Abstract

Burkitt lymphoma (BL), an aggressive B-cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi-centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high-risk BL registered on Children's Cancer Group study CCG-5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5-year overall survival (77% vs. 95%, P = 0.012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.

Figures

Figure 1

FISH analysis for the detection of MYC rearrangement, deletion of 13q and gain of chromosome 7. (A) Schematic display of Vysis LSI® MYC Dual Color, Break Apart probe, centromeric portion labeled in SpectrumOrange™ and telomeric portion labeled in SpectrumGreen™. (B) Schematic display of Vysis LSI® D13S319 (13q14.3) probe labeled in SpectrumOrange™, Vysis LSI® 13q34 probe labeled in SpectrumGreen™. (C) Schematic display of Vysis CEP® 7 (D7Z1) probe labeled in SpectrumAqua™. (D) Interphase nuclei demonstrating rearrangement of the MYC dual color, break apart probe as indicated by one colocalized (fused) orange and green signal, 1 separate orange signal and 1 separate green signal. (E) Interphase nuclei demonstrating deletion of LSI 13q14.3 and normal copy number for LSI 13q34 as indicated by 1 orange signal and 2 green signals. (F) Interphase nuclei demonstrating gain of CEP 7 and normal copy number of LSI 13q14.3 and 13q34 as indicated by 3 aqua signals, 2 orange signals and 2 green signals. (D-F shown at x100 original magnification)

Figure 2

Event-free survival (EFS) and overall survival (OS) for various patient groups with 13q loss. P-values for OS among patient groups “unspecified del(13)” and “del(13)(q14)” fall below 0.05, demonstrating an association with these groups and decreased OS.

Figure 3

Unvivariate analysis of 5-year OS in 90 children and adolescents with intermediate and high-risk Burkitt lymphoma. (A) OS with and without deletion of chromosome 13. (B) OS with and without deletion of 13q14.3.