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A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma
Abstract:
The genomes of various tumour cells contain mutant oncogenes that act dominantly, in that their effects can be observed when they are introduced into non-malignant cells. There is evidence for another class of oncogenes, in which tumour-predisposing mutations are recessive to wild-type alleles. Retinoblastoma is a prototype biological model for the study of such recessive oncogenes. This malignant tumour, which arises in the eyes of children, can be explained as the result of two distinct genetic changes, each causing loss of function of one of the two homologous copies at a single genetic locus, Rb, assigned to the q14 band of human chromosome 13. Mutations affecting this locus may be inherited from a parent, may arise during gametogenesis or may occur somatically. Those who inherit a mutant allele at this locus have a high incidence of non-ocular, second tumours, almost half of which are osteosarcomas believed to be caused by the same mutation. Here we describe the isolation of a complementary DNA segment that detects a chromosomal segment having the properties of the gene at this locus. The gene is expressed in many tumour types, but no RNA transcript has been found in retinoblastomas and osteosarcomas. The cDNA fragment detects a locus spanning at least 70 kilobases (kb) in human chromosome band 13q14, all or part of which is frequently deleted in retinoblastomas and osteosarcomas.
Insights
Researchers identified a gene linked to retinoblastoma and osteosarcoma. This gene, located on chromosome 13, is frequently deleted in these childhood cancers, suggesting its role as a recessive oncogene.
Area of Science:
- Molecular biology
- Human genetics
- Cancer research
Background:
- Some oncogenes are dominant, while others, like those predisposing to tumors, are recessive.
- Retinoblastoma, a childhood eye cancer, serves as a model for studying recessive oncogenes.
- This cancer results from loss-of-function mutations in both copies of the Rb gene on chromosome 13.
Purpose of the Study:
- To isolate a complementary DNA (cDNA) segment that identifies the gene associated with the Rb locus.
- To investigate the expression and chromosomal location of the gene implicated in retinoblastoma and osteosarcoma.
Main Methods:
- Isolation of a complementary DNA (cDNA) segment.
- Detection of a chromosomal segment with properties of the Rb gene.
- Analysis of gene expression in various tumor types.
- Assessment of chromosomal deletions in retinoblastomas and osteosarcomas.
Main Results:
- A cDNA segment was isolated, identifying a gene at the Rb locus on human chromosome 13q14.
- The gene is expressed in numerous tumor types but shows no RNA transcript in retinoblastomas and osteosarcomas.
- The identified locus spans at least 70 kilobases (kb) and is frequently deleted in these specific cancers.
Conclusions:
- The isolated cDNA corresponds to the gene at the Rb locus.
- Loss of this gene function through deletion is implicated in the development of retinoblastoma and osteosarcoma.
- This finding supports the role of recessive oncogenes in cancer etiology.