Neuroblastoma tumour genetics: clinical and biological aspects

Abstract

Neuroblastoma tumour cells show complex combinations of acquired genetic aberrations, including ploidy changes, deletions of chromosome arms 1p and 11q, amplification of the MYCN oncogene, and-most frequently-gains of chromosome arm 17q. Despite intensive investigation, the fundamental role of these features in neuroblastoma initiation and progression remains to be understood. Nonetheless, great progress has been made in relating tumour genetic abnormalities to tumour behaviour and to clinical outcome; indeed, neuroblastoma provides a paradigm for the clinical importance of tumour genetic abnormalities. Knowledge of MYCN status is increasingly being used in treatment decisions for individual children, and the clinical value of 1p and 17q data as adjuncts or refinements in risk stratification is under active investigation. Reliable detection of these molecular cytogenetic features should be regarded as mandatory for all new cases at presentation.

Figure 1 (A) G-banded metaphase chromosomes 1 showing a large deletion including the p36 band. (B) Two colour interphase fluorescent in situ hybridisation (FISH) detection of 1p deletion; tumour nuclei showing two centromeres for chromosome 1 but only a single signal for 1p36. (C) Comparative genomic hybridisation (CGH) profile; the shift in the fluorescence ratio profile indicates that a large segment of 1p (indicated by red bar) is absent from the tumour genome. (D) genomic PCR analysis of two 1p36 alleles in a neuroblastoma tumour (t) and the patients constitutional DNA (c); deletion at marker D1S76, marker D1S80 was not informative (constitutionally homozygous). (E) double minute chromosomes in a tumour metaphase. (F) interphase FISH showing a MYCN amplified nucleus. (G) Appearance of MYCN amplification by CGH: excess tumour DNA is present binding to the 2p24 locus of MYCN. (H) Southern blot detection of MYCN status (image courtesy of J Board); lanes 1–3 non-amplified tumours, lane 4 showing MYCN amplification. (I) Two examples of unbalanced translocations resulting in gain of distal 17q segments. (J) Interphase FISH analysis of chromosome 17; tumour nuclei showing two signals for chromosome 17p and three signals for distal 17q. (K) CGH profile showing gain of 17q.

Figure 2 (A) Unbalanced translocation der(1)t(1;17)(p36;q21) resulting in concurrent loss of 1p36 and gain of 17q21–qter. (B) Association between 1p, 17q, and MYCN in 260 neuroblastoma primary tumours (data from Bown et al).⁵³

Figure 3 (A) Incidences of genetic abnormalities (1p deletion, MYCN amplification, and 17q gain) within tumour stages. (B) Correlation between tumour genetic features and clinical outcome in 260 cases (data from Bown et al).¹⁵¹