A new study demonstrates how esophageal adenocarcinoma evolves during a 4-year period as a dynamic, stochastic process of punctuated equilibrium followed by catastrophic genomic doubling.
The study was published online November 19 in Cancer Prevention Research.
Until recently, scientists have believed that neoplastic evolution is a gradual and linear process. However, screening strategies built on this flawed paradigm have grossly failed in their efforts at early cancer detection, lead investigator Brian J. Reid, MD, from the Division of Human Biology and the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington, told Medscape Medical News.
"The vast majority — about 95% — of patients who develop esophageal adenocarcinoma do so outside of screening and surveillance, while most — again, about 95% — under surveillance do not develop esophageal cancer and die of other causes," Dr. Reid pointed out.
"We as clinicians must stop scaring our patients," Dr. Reid emphasized, noting that only about 5% of reflux patients are diagnosed with Barrett’s esophagus on endoscopy, and of those, only a minuscule proportion (0.3% - 0.7%) progress to cancer each year.
"Primary care doctors should have a fact sheet telling patients that if you have heartburn your chances of adenocarcinoma are very small, and that you can be screened or not screened, but there is no cure for Barrett's, and if you test positive you will be buying into repeated endoscopies for the rest of your life," Dr. Reid pointed out. This problem of overdiagnosis of indolent conditions while underdiagnosing fatal disease is a big issue in the medical world, he commented.
"In the meantime, physicians also have to recognize and stop using the word cancer because all it does is scare the patient," Dr. Reid added, concluding, "After you tell a patient that they have Barrett's and that only a very small minority develop cancer, just stop. Stop and acknowledge that you said a very scary word, 'cancer,' and make sure that the patient has heard the entire sentence."
Analysis of Chromosome Alterations
To document how esophageal cancer evolves, Dr. Reid and colleagues analyzed somatic chromosomal alterations by single nucleotide polymorphism array over the course of more than 20,425 person-months of follow-up in 248 patients with Barrett's esophagus.
The team found that a large majority of patients (69%) were "nonprogressors" who exhibited a pattern of small localized deletions involving fragile sites and 9p loss/copy neutral losses of heterozygosity that yielded little genetic diversity and remained relatively stable over time.
"We had a large population with small mutations in general, small homozygous deletions of pieces of DNA, and they basically remained stable as a population over up to 2 decades. They weren't slowly increasing at all, they were remaining stable as a population: Maybe one patient would go up a little bit, another would go down a little bit, but there were no dramatic changes in the people who did not progress to cancer," Dr. Reid said.
In contrast, the remaining 31% of patients were described as "progressors," and they diverged from the general pattern about 3 to 4 years before cancer diagnosis, as evidenced by a shift from small losses on chromosome 18 to gains/losses of large chromosomal regions and even whole chromosomes.
"These occurred in a somewhat coordinated manner, such as you would have recurrent losses on human chromosomes 17, 15, 13, but not on other chromosomes," Dr. Reid pointed out.
Then, in the last 24 months before diagnosis, the problem of high genomic divergence was compounded by a doubling effect.
"In the last 24 months before cancer, we saw a sudden change — suddenly the genomes were extremely abnormal — and we found that the cells had undergone a genome doubling, such that single surviving chromosome 17s were now being replicated. And that was occurring right before the development of cancer," Dr. Reid emphasized.
The findings explain why current strategies grossly fail to detect cancer in patients diagnosed with Barrett's esophagus, Dr. Reid said. Laboratories could develop tests to pick up high-risk Barrett's esophagus on the basis of chromosomal abnormalities, but changing the way physicians do things will take time, and maybe future research will also extend the window of detection, he commented.
The authors have disclosed no relevant financial relationships.
Cancer Prev Res. Published online November 19, 2013. Full text
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