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Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours
Insights
Genetic alterations in chromosome 11p are linked to childhood Wilms' tumours. Molecular analysis revealed somatic deletions and duplications in tumour cells, suggesting a common mechanism in embryonal cancers.
Area of Science:
- Tumour biology
- Paediatric oncology
- Molecular genetics
Background:
- The AGR triad syndrome is associated with germ-line deletions on chromosome 11p (11p13) and early Wilms' tumour development.
- Knudson's hypothesis suggests somatic deletions on 11p may also drive isolated Wilms' tumours.
- Previous studies showed inconsistent chromosomal deletions in isolated Wilms' tumours.
Purpose of the Study:
- To investigate somatic genetic alterations at 11p loci in Wilms' tumour cells using a molecular genetic approach.
- To determine if specific gene deletions occur somatically in Wilms' tumours.
- To explore the relationship between chromosomal changes and embryonal cancers in children.
Main Methods:
- Molecular genetic analysis of Wilms' tumour cells.
- Detection of somatic deletions at specific 11p loci.
- Analysis of allele-specific copy number changes.
Main Results:
- Somatic deletions of specific genes were identified in four out of six Wilms' tumours.
- In all cases with deletions, duplications leading to homozygosity of non-deleted alleles were observed.
- These findings suggest a potential two-hit mechanism involving deletions and duplications.
Conclusions:
- Somatic genetic alterations, including deletions and duplications, at 11p loci are implicated in Wilms' tumour development.
- The observed genetic events may be a common mechanism underlying various embryonal tumours in children.
- This study provides molecular insights into the pathogenesis of paediatric embryonal cancers.
Abstract:
One of the most provocative findings in tumour biology is the relationship between chromosomal changes and embryonal cancers in children. For example, children with the rare paediatric syndrome AGR triad (aniridia, genito-urinary abnormalities and mental retardation) often develop Wilms' tumours at a very early age and carry a germ-line deletion on the short arm of chromosome 11 (11p13). It has been suggested that the germ-line deletion 11p is the first of two or more steps to cancer in AGR children. If this were true, one might expect a similar deletion to arise somatically in the far more common isolated Wilms' tumours of children without AGR, as suggested by Knudson from epidemiological data. However, a chromosomal deletion on 11p was observed in only two of five such cases, while it was absent or seen inconsistently in others. We have now used a molecular genetic approach to determine whether Wilms' tumour cells possess somatic alterations at 11p loci. We have found somatic deletions of specific genes in four of six Wilms' tumours. Surprisingly, in all four cases, the deletions were associated with duplications leading to homozygosity of the non-deleted alleles in the tumour cells. As analogous observations were recently reported in retinoblastoma, the genetic events reported here may underlie the development of many such embryonal tumours in children.