Association of a specific chromosomal abnormality with tumor type is well established and may reflect mechanisms of oncogenesis peculiar to that tumor. Alternatively, it may be that these associations reflect the particular differentiated state of the malignant cell, consistent with the model that rearrangements occur only within chromatin in an """"""""active"""""""" configuration. Our focus this year is on abnormalities of human chromosonome 14 in """"""""normal"""""""" and malignant lymphocytes. Previously we identified the formation of T-cell receptor (TCR) alpha chain immunoglobulin heavy (IgH) chain hybrids as a consequence of the inversion of chromosome 14 in both a T and B cell malignancy. This inversion appeared to be morphologically identical to the occasional inversion of this chromosome in the cells of all normal individuals. We have investigated the frequency of the normal occurance of this sporadic abnormality. We are using the polymerase chain reaction to develop a rapid means of assessing the molecular nature of these sporadic but consistent events. A related but distinctive inversion or translocation of chromosome 14 is most likely associated with a particular type of T-cell malignancy, as well as with a clonal proliferation of T-cells in patients with the disease, ataxia-telangiectasia. We are cloning and characterizing the chromosome 14 breakpoints from T-cells from a patient with ataxia-telangiectasia and from a cell line derived from a patient with a particular T-cell lymphoma. The proximal breakpoints in both these cases is again (as above) within the TCR alpha locus. The distal breakpoints do not appear to involve IgH, but rather identify a more proximal region perhaps containing a new growth effecting gene function. This research, utilizing our full complement of research tools, (cell culture, chromosome in situ, basic molecular biology) leads to the understanding of the fundamental issue of chromosome instability and its impact on oncogenes.
