DNA repair

Celeste et al.(2003)


DNA repair

Dumon-Jones et al. (2003)


DNA repair

Srivastava et al.(2003)

Figure 4.4

Genetic heterogeneity of LOH regions (depicted by black capped bars) may explain the failure to find the "neuroblastoma suppressor gene." In case of genetic heterogeneity, there could actually be at least two (B, C), if not more genes involved, and these might be separated many megabases from each other. Combining these LOH regions into a single consensus region (A) would inevitably initiate a gene search in a region that is unlikely to harbor the long-sought NSG

According to this hypothesis, there would actually be two SROs, each harboring a different gene that is damaged only in tumors of the corresponding group. As mentioned above, previous studies have indicated that two, or even more, "neuroblastoma genes" may reside in chromosome 1p (Caron et al. 2001). The existence of two separate 1p regions with relevance to neuroblastoma is also supported by an independent study that indicated two regions of loss, at 1p36 and 1p22 (Mora et al. 2000). Another study concluded that there were three regions of loss at 1p36.1-2,1p36.3, and 1p32-34, and each was associated with different neuroblastoma groups (Hiyama et al. 2001).

4.5 Comparative Genomic Hybridization

In CGH, differentially labeled tumor DNA and normal DNA are competitively hybridized to normal human metaphase chromosomes (Kallioniemi et al. 1992). This methodology detects quantitative chromosomal changes, such as deletions, duplications or amplifications on the basis of the ratio of the hybridization of the two differently labeled DNAs. The advantage of this approach is that the complete set of quantitative genomic changes can be determined in a single experiment. Limitations are the low level of resolution (several Mb) and the fact that absolute quantitation of the changes is not precise. More recently, array CGH has been performed in an effort to increase the resolution of this technique. This strategy utilizes an array of DNA targets, and both cDNA and BAC arrays have been used (Beheshti et al. 2003; Cowel and Nowak 2003).

Both CGH and array CGH (Cunsolo et al. 2000; Plantaz et al. 2001; Schleiermacher et al. 2003; Stallings et al. 2003; Vettenranta et al. 2001) have largely confirmed previous cytogenetic and LOH studies revealing a high-frequency of 1p loss, 11p loss, 2p gain, and 17q gain (Schleiermacher et al. 2004; Brinkschmidt et al. 1997; Lastowska et al. 1997b, 2002; Plantaz et al. 1997; Vandesompele et al. 1998). The CGH studies have also revealed that about 50% of neuroblastomas have an additional segment of 17q, indicating that gain of 17q is the most frequent genetic alteration in neuroblastoma. Gain of 17q ap pears more common in advanced-stage tumors, in tumors from children aged over 1 year, and in tumors showing 1p loss, amplified MYCN, and diploidy or tetraploidy. In contrast,triploidy with whole chromosome 17 gain is associated more often with neuroblastomas showing favorable clinical and genetic features (Bown et al. 1999). Amplified MYCN rarely, if ever, occurs without either 1p deletion or 17q gain or both, implying that MYCN amplification is a later event in the sequence of genetic aberrations underlying neuroblastoma progression (Bown et al. 1999). Although several studies appear to suggest 17q gain as a powerful prognostic factor (Abel et al. 1999; Bown et al. 1999,2001; Caron 1995; Caron et al. 1996; Lastowska et al. 1997a), a recent study could not confirm this association (Spitz et al. 2003).

4.6 Tumor Cell Ploidy

Many neuroblastomas have higher than normal DNA content or hyperploidy. Kaneko and Knudson have suggested that in neuroblastoma, aneuploidy may be a consequence of tetraploidization with subsequent bipolar, tripolar, or tetrapolar divisions (Kaneko and Knudson 2000). Supernumerary centrosomes leading to multipolar divisions have been implicated in both chromosome missegregation and the generation of aneuploid cells in various cancer types, including neuroblastoma (Brinkley 2001). A defect of spindle formation may cause incomplete segregation during mitosis; thus, such a defect in a tetraploid cell undergoing a tripolar division could lead to one near-triploid and one near-pentaploid cell. In fact, in neu-roblastoma tumors with more than one tumor cell clone,near-pentaploid tumor cells are often observed together with near-triploid tumor cells.

Recently, Kaneko and Knudson have developed an attractive hypothesis explaining the association between ploidy and neuroblastoma phenotype (Kaneko and Knudson 2000). This hypothesis is based on the assumption that both clinically "favorable" triploid tumors and clinically "unfavorable" diploid tumors arise through the same genetic event, as suggested from observations in familial cases (Knudson and Strong 1972; Kushner et al. 1986). The initiating tumorigenic event may be a mutation in a classical tumor suppressor gene with recessive effect at cellular level (Comings 1973; Knudson and Strong 1972). Tetraploidization and subsequent multipolar division of a diploid cell heterozygous for a mutation in such a gene would give rise to diploid and tetraploid daughter cells with no normal allele and highly malignant phenotype, or triploid daughter cells with at least one normal allele and less malignant phenotype.

4.7 Conclusion

Despite many advances in understanding the genetics and developmental molecular pathways,they have not yet translated into more effective therapy for high-risk neuroblastoma Nevertheless, the fascinating multiplicity of its clinical and biological pheno-types has attracted a growing number of clinical and basic scientists. Their combined efforts will inevitably resolve the intricate pathways that govern both progression and spontaneous regression of this disease. This knowledge should provide the platform for the development of new diagnostic tools and novel therapeutic strategies. Until then, we should be careful and avoid offering simplified suggestions for a rapid clinical translation.

Acknowledgements. Work in the author's laboratory was supported by grants from the Deutsche Krebshilfe, Sander Stiftung, Bundesministerium für Forschung und Technology, and by DKFZ-MOS (Israel) cooperation.


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