APPLICATION OF MOLECULAR-GENETICS AND CYTOGENETICS TO BREAST-CANCER AND SOFT-TISSUE SARCOMAS

Background: Over the last decade there have been considerable advances in understanding of the molecular events involved in the initiation and progression of a wide range of solid tumours. In many instances, cytogenetic abnormalities have been the first indication that there is a mutated gene at a particular locus. In colonic polyposis, for example, the loss of 5q material in a man with the disease indicated the importance of the region and led to the subsequent cloning of the gene. Interestingly, loss of this tumour supressor gene is also seen in approximately 20%-50% of sporadic colorectal carcinomas, which suggests that it may be important to study these inherited syndromes to identify genes that may be more widely involved in carcinogenesis. It is also important to realize that the order in which different molecular events occur is unlikely to fit into predictable chronological patterns, and that there will be great variation in the molecular defects of tumours that otherwise appear morphologically similar and have a common pattern of clinical presentation and progression. This is because established tumours are probably composed of a number of subclones at the molecular level, and clonal selection will only take place if a particular mutation provides a selective growth advantage or it is necessary for a stage in progression, such as invasion or metastasis. Multiple sites of loss of heterozygosity (LOH) have been identified in a range of tumours, many of which may be sites of as yet unidentified tumour supressor genes. In the case of breast cancer, LOH is so common that a 15% loss at any particular locus is considered to be a random event and merely an indication of an unstable genome. The difficulty is, therefore, to differentiate the critical molecular events in tumorigenesis from the epiphenomena. Probably the only approach is to examine early lesions, in the case of breast cancer by microdissection of in situ disease and atypical lesion. It is possible, using material from paraffin blocks, to look for LOH and, using the new technique of comparative genomic hybridization, to identify consistent areas of gene amplification and areas of chromosome loss. In some tumour types, such as soft tissue sarcomas, however, the molecular abnormalities appear to be more restricted, often only apparently involving a single chromosome translocation and a few secondary changes. As these tumours have the same malignant characteristics as the more common epithelial tumours, future comparative studies of such diverse tumour groups, in relation to their biological behaviour, can be expected to provide important information on the common and critical pathways involved in carcinogenesis.