June 18, 1999 Sophisticated computational tools developed to trace species evolution by comparing DNA sequences have now been used to track the development of human cancer.
The collaboration by a USC team led by cancer researcher Darryl Shibata and computational biologist Simon Tavare casts doubt on conventional wisdom regarding the relationship between colorectal cancers (carcinomas) and the polyps (adenomas) which typically precede them.
The preliminary findings, if they can be confirmed, may have clinical significance in considering non-surgical options for treating polyps.
According to Shibata, an associate professor in the USC medical school department of pathology, oncologists have long believed that the development of colon cancer is a progressive and linear process, with a normal cell mutating into adenoma, and the adenoma subsequently mutating further into carcinoma. In this conventional model, the adenoma is the direct precursor or ancestor to the carcinoma.
But according to the new study, published in the June issue of the American Journal of Pathology, genetic evolution analysis indicates that adenoma and carcinoma lines can arise from a common precursor but subsequently develop in parallel. In this scenario, the adenoma is not the "mother" of the carcinoma but rather a cousin.
The finding suggests that the direct progenitor of cancer cells may not be the most prevalent cell in a polyp. The clone comprising the majority of cells in the adenoma is genetically a dead end with respect to the cancer. One important consequence is that in some cases cancer may arise without being preceded by polyps at all, that is, "the true progenitor may be occult," according to Shibata.
The researcher notes that precisely this scenario is sometimes seen when a patient with no symptoms or polyps at one examination is found a year later to have developed colon cancer. Traditionally, it had been thought that the initial examination simply missed finding polyps or that evolution from a polyp to a cancer occurred faster than usual.
The analysis was possible because the abnormal colon cells studied, adenomas and carcinomas alike, all share a specific mutation that destroys the cell's ability to edit and repair errors in DNA replication. As a result, such cells accumulate such errors at a rapid and constant rate.
"This gives us a mutational clock, which we can use to keep track of progressions in the daughter cell lines," says Shibata. The frequency of the changes allows current genetic technology to compare easily cell lines through successive generations in specific non-coding parts of the human genome known as microsatellites.
The genetic sequences analyzed normally change very slowly, and cells from most kinds of cancer wouldn't be expected to accumulate many changes in the lifetime of their human hosts. But such changes do occur and accumulate in successive generations of normal cells over geologic time. This is where Tavare, the George and Louise Kawamoto Chair In Biological Sciences and professor of mathematics in USC's college of letters, arts & sciences, had learned to analyze them to study the history of species.
As the universal informational molecule, DNA sequences can be analyzed and compared regardless of their origins. "While changes that would normally accumulate over millennia in normal cells accumulate over months in these mismatch repair deficient tumor cells," says Tavaré, "they can be analyzed using similar mathematical techniques."
The analysis, done on a number of cell samples from three different patients, shows that, at least in this group of samples, the carcinoma cells and adenoma cells had diverged far back in the cell lineage, long before carcinoma was seen.
Because polyps are routinely removed when found, the findings don't suggest great changes in clinical approach to disease, says Shibata "as physical removal would eliminate both occult and overt potential cancer precursors. However, attempts to shrink polyps with chemotherapy may not prevent cancer," since if the new analysis is correct, reductions in the sizes of polyps may reflect efficacy against the adenoma dead-ends and not in the extinction of the actual cancer lineage.
Shibata began the research after reading about work in computational biology and thinking that the techniques might be applicable to oncology, made contact with Tavare, an international authority on development of computational techniques in molecular evolution.
Extensive meetings were necessary to make the experiment work: "He knew so little about the way tumors grow, and I knew so little about his methods," said Shibata.
However, Shibata hopes to continue to work with Tavare and others to refine his technique to attempt to shed light on development of metastases, the deadly colonies sent out by initial growths. They want to ask, are these descendents of the early cancer line or are they only produced at a late stage of tumor development?
Shibata notes that current techniques can take advantage of powerful animal models, although "mice don't live long enough to match the time scale of human tumor evolution" he said.
But he is excited by the prospects opened by the work, which he says is the first time the full sophistication of the techniques developed to track evolutionary changes have been used to study cancers.
Collaborating with Shibata and Tavare were Jen-Lin Tsao of the USC Norris Cancer Center department of pathology, Reijo Salovaar and Lauri Aaltonen of the University of Helsinki department of pathology and medical genetics, Helsinki, Finland; and Jeremy R. Jass, of the University of Queensland, Medical School, Herston, Australia.
The research was supported by grants from the National Institutes of Health and the National Science Foundation.
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