Chromosome studies of solid tumours.

Introduction Cytogenetic analysis of malignant cells very often indicates acquired chromosome changes-that is, deviations from the normal constitutional 46,XX or 46,XY karyotype. Much of what we know about these changes is derived from studying leukaemias and lymphomas. Many of these abnormalities are nonrandom, and particular chromosome changes are consistently found in particular disease types. These abnormalities may be of chromosome structure (translocations, deletions, inversions, etc) or of chromosome number (monosomies, trisomies, etc). The recurrent finding of such specific, clonal karyotype abnormalities underlies the integral role of cytogenetics in the clinical investigation of preleukaemias, leukaemias, and lymphomas. Depending on the specificity of the particular chromosome abnormality, cytogenetics can provide powerful confirmatory evidence in diagnosis, and is occasionally of prime importance in defining disease type. As the disease progresses, secondary karyotype changes may appear; where such clonal evolution pathways are well characterised-for example, in chronic myeloid leukaemia'-cytogenetics can be used to stage the disease and monitor malignant progression. For both lymphoid and myeloid disorders, significant correlations have also been established between the chromosome changes seen in the bone marrow at presentation and the patient's prognosis in terms of response to treatment and survival.2 4 Over the past two decades, cytogenetic studies in haematological malignancies have also contributed to profound advances in the understanding of oncogenesis: the existence of recurring chromosome breakpoints implies the presence, at discrete loci, of genes that are important in the development of cancer. In several diseases molecular studies have elucidated the mechanisms whereby chromosome rearrangements result in oncogene activation or alteration.5 6 The cytogenetic investigation of solid tumours is at a much less advanced stage. The reasons for this are largely technical: many tumours contain areas of necrosis or show low mitotic activities; and tissue cultures often fail to accumulate sufficient numbers of mitotic cells of suitable quality for chromosome analysis. Problems also arise in disaggregating the material to produce the cell suspensions required for direct harvests of metaphase cells and for short term cultures. Improvements have been reported in the yield of metaphase cells following tumour disaggregation with enzymes such as collagenase.7 The cytogenetics of solid tumours is currently the subject of intense investigation, and the rate of accumulation of data now makes a single brief review impossible. What follows is heavily biased towards tumours occurring in children, reflecting the author's research interest. It is not yet clear whether karyotype studies of solid tumours will prove, like leukaemia cytogenetics, to be of routine clinical use, but several disease specific chromosome aberrations have now been described (table). Correlations with prognosis and links with molecular changes of oncogenic importance have also been established. Sandberg and Turc-Carel89 have indicated several areas in which solid tumour cytogenetics has already proved valuable: (a) Defining subsets within a histologically homogenous tumour type-for example, those showing i(5p) or del(5q), + 7, 9 or del (9p) in transitional cell carcinoma of the bladder. (b) Suggesting aetiological connections between histologically diverse tumours-for example, virtually all germ cell tumours of the testis, both teratomas and seminomas, have been found to show i(12p). (c) Highlighting known histological subtypesfor example, the t(12; 16) translocation specific to the myxoid form of liposarcoma. (d) Suggesting a primary tumour site when a specific karyotype change is found in a metastatic tumour or in bone marrow. When considering chromosome changes in solid cancers, it is possible, as in leukaemias and lymphomas, to distinguish between those of primary aetiological importance and secondary changes appearing in the course of tumour progression. For a given tumour type the former are recognised either because they are seen as the sole karyotype abnormality or because they recur as a common link between more complex abnormal karyotypes which may include multiple secondary rearrangements. Sequential cytogenetic changes have been recorded in a variety of solid tumours as they develop from relatively benign forms to show more malignant, invasive, or metastatic behaviour. For example, Nowell has summarised the current knowledge of cytogenetic evolution in melanocytic tumours and in colon cancer.10 In the former, karyotypically abnormal clones are more common as the disease progresses from common naevus, through dysplastic naevus, to invasive and metastatic melanoma, with 9p and 1Oq rearrangement in early stages and Department ofHuman Genetics, University of Newcastle upon Tyne, 19-20 Claremont Place, Newcastle upon Tyne NE2 4AA N P Bown Correspondence to: N P Bown