Chromosome translocations and cancer

Published on September 30, 2015   45 min

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Other Talks in the Series: Cancer Genetics

I am Felix Mitelman at the University of Lund, in Sweden. And my lecture will be on the role played by chromosome translocations in cancer development. I will also briefly discuss the clinical significance of translocations as diagnostic and prognostic tools in the management of cancer patients. And finally, I will present some remaining questions as to how, when and why the aberrations are formed.
But first, a historical background as an introduction. And an appropriate starting point is 100 years ago in 1914, when Theodor Boveri in this famous book, in English, on the origin of cancer presented a conceptually new idea, which later became known as the somatic mutation theory of cancer.
Boveri proposed that cancer originates in a single cell by mitotic disturbances resulting in chromosome aberrations. Through subsequent cell divisions, this acquired genetic change is propagated to all daughter cells. And as a consequence, all cells in a cancer carry the genetic abnormality that initiated this process. This remarkably prescient idea still today remains the paradigmatic view of cancer pathogenesis supported by a wealth of experimental evidence. But it long remained a theoretical idea, which could not be examined critically until technical improvements in human cytogenetics were made half a century later, and led to the description in 1956
of the normal human chromosome complements by Tjio and Levan in Lund, Sweden.
Only four years later in 1960, Peter Nowell and David Hungerford, in Philadelphia, presented the first evidence supporting Boveri's idea. They showed that patients with chronic myeloid leukemia consistently had a small acquired marked chromosome in their bone marrow cells. One of the smallest chromosomes, number 21 or 22, this could not be determined at the time, seemed to have lost a piece of its long arm. This first characteristic chromosome change in the human malignancy soon designated "Philadelphia chromosome" after the city where it had been discovered, immediately provided a very strong support for the idea that chromosome aberrations indeed may play a major role in the initiation of the carcinogenic process. This seemed to be the true verification of Boveri's somatic mutation theory. It was reasonable to assume that the acquired specific chromosomal abnormality, a perfect example of a somatic mutation in hematopoietic bone marrow cell or stem cell was the direct cause of the neoplastic state. The discovery of the Philadelphia chromosome greatly stimulated interest in cancer cytogenetics in the 1960s. But the results obtained for more than 10 years were quite disappointing. Chromosomal abnormalities were indeed found in most tumors, but no new specific aberration comparable to the Philadelphia chromosome was detected. The aberrations that were found varied among patients with the same tumor types. And so at the end of the 1960s, most scientists agreed that chromosomal abnormalities were secondary epiphenomena, not the cause, but the consequence of neoplasia. The Philadelphia chromosome seemed to be the exception to the rule that chromosome change did not play any important pathogenetic role in carcinogenesis. And as a result, the interest in cancer cytogenetics gradually faded away.
The situation changed dramatically with the introduction of chromosome banding by Caspersson and Zech in 1970. With this new technique, characteristic alternate dark and light stained bands could be produced on each chromosome. And now every chromosome and chromosome region could be precisely identified on the basis of its unique banding pattern. The technology revolutionized cytogenetics. Aberrations that previously had not been possible to see could now be identified and characterized at precedented resolution level.
Very soon, the first reports of subtle, previously undetectable translocations appeared. In 1973, Janet Rowley in Chicago showed that the Philadelphia chromosome in chronic myeloid leukemia actually originated through a translocation between chromosomes 9 and 22. The distal part of the long arm of chromosome 22 was not deleted, as had been previously thought, but was found to be translocated to the end of the long arm of chromosome 9.

Chromosome translocations and cancer

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