A method called chromosomal breakpoint analysis was the means by which the team drew inferences about the relationships between various tumor cell subpopulations. "The history of the cell is written in these breakpoints," explains Hicks. "They are the product of mutational events, the rearrangements of DNA that have occurred, and they don't go away." Generally speaking, these events are additive, a key concept that enabled the CSHL team to say that the genetic provenance of a cell is written in its DNA. The evolutionary history of the polygenomic tumor sample studied was traced by tracking 657 distinct chromosomal breakpoints. Tumor cells of all three clonal "subspecies" shared about half the mutational events; only a fraction shared another significant number of mutations; and a still smaller fraction shared yet another wave of mutations.
A significant fraction of tumor cells up to 30% -- contained some combination of DNA deletions and additions that made them appear normal, in terms of their total DNA content. These cells, called "pseudodiploid" by the researchers, appear to be cancerous but are not part of the major clonal expansions. The team's method provides the first means of identifying such cells, which are not distinguishable using conventional methods of tumor characterization. One hypothesis holds that such cells are potential sources of future clonal events; another, that they may be important in the process of metastasis.
"We want to learn how a metastasis grows," said Hicks, "and we now have the ability to do that at a very detailed level. In a typical blood draw taken from a cancer patient, you will typically see between five and 20 circulating tumor cells, a mark of metastasis. We'll be able to look at every one of them and see if, for example, there's a new clone that is different from the cell populati
|Contact: Peter Tarr|
Cold Spring Harbor Laboratory