| Genetics Index | Glossary |
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Translocation Breakpoints and Cancer |
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Chromosomal translocations bring two previously unlinked segments of the genome together, which in some cases can result in disease by inducing inappropriate expression of a protein or synthesis of a new fusion protein. This phenomenon is particularly important when the breakpoint of the translocation affects an oncogene and results in cancer. In fact, the study of translocations in neoplastic cells provided some of the best early evidence in support of a genetic basis for cancer. In virtually all cases of chronic myelogenous leukemia in man, a specific translocation is seen. This translocation was shown to involve reciprocal fusion of rather small pieces from the long arms of chromosome 9 and 22. The altered chromosome 22 is known as the Philadelphia chromosome (abbreviated as Ph1). When the breakpoint of the Ph1 chromosome was sequenced, it was found that this translocation creates a fusion gene by bringing together sequences from the c-abl proto-oncogene and another gene called bcr (for breakpoint cluster region). The bcr-abl fusion gene encodes a phosphoprotein (p210) that functions as a disregulated protein tyrosine kinase and predisposes the cell to become neoplastic. This hypothesis was strongly supported by finding that expression of p210 results in transformation of a variety of hematopoietic cell lines in vitro and that mice transgenic for the human bcr-abl gene developed a number of hematologic malignancies, prominent among them a syndrome very much like CML. Another well studied example of a translocation generating cancer is seen in Burkitt's lymphoma. In most cases of this B cell tumor, a translocation is seen involving chromosome 8 and one of three other chromosomes (2, 14 or 22). In these cases, a fusion protein is not produced, but rather, the c-myc proto-oncogene on chromosome 8 is brought under transcriptional control of an immunoglobulin gene promoter. In B cells, immunoglobulin promoters are transcriptionally quite active, resulting in overexpression of c-myc, which is known from several other systems to have oncogenic properties. Hence, this translocation results in abberent high expression of an oncogenic protein, which almost certainly is at the root of the Burkitt's tumor. Other examples of translocation breakpoints associated with human cancer include:
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Last updated on January 16, 1996 |
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