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 a nd progression of a wide range of solid tumours. In many instances, cy togenetic 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 impo rtance of the region and led to the subsequent cloning of the gene. In terestingly, loss of this tumour supressor gene is also seen in approx imately 20%-50% of sporadic colorectal carcinomas, which suggests that it may be important to study these inherited syndromes to identify ge nes that may be more widely involved in carcinogenesis. It is also imp ortant to realize that the order in which different molecular events o ccur is unlikely to fit into predictable chronological patterns, and t hat there will be great variation in the molecular defects of tumours that otherwise appear morphologically similar and have a common patter n of clinical presentation and progression. This is because establishe d tumours are probably composed of a number of subclones at the molecu lar level, and clonal selection will only take place if a particular m utation 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 tum ours, many of which may be sites of as yet unidentified tumour supress or genes. In the case of breast cancer, LOH is so common that a 15% lo ss at any particular locus is considered to be a random event and mere ly an indication of an unstable genome. The difficulty is, therefore, to differentiate the critical molecular events in tumorigenesis from t he epiphenomena. Probably the only approach is to examine early lesion s, in the case of breast cancer by microdissection of in situ disease and atypical lesion. It is possible, using material from paraffin bloc ks, to look for LOH and, using the new technique of comparative genomi c hybridization, to identify consistent areas of gene amplification an d areas of chromosome loss. In some tumour types, such as soft tissue sarcomas, however, the molecular abnormalities appear to be more restr icted, often only apparently involving a single chromosome translocati on and a few secondary changes. As these tumours have the same maligna nt characteristics as the more common epithelial tumours, future compa rative studies of such diverse tumour groups, in relation to their bio logical behaviour, can be expected to provide important information on the common and critical pathways involved in carcinogenesis.