Future Implications

The endometrial experience highlights the problems and benefits of a disease model increasingly dominated by a molecular perspective. Interacting disease mechanisms may intersect in hormonal selection of PTEN-mutant endometrial clones. Observed clinical outcomes reflect the balance of all of these factors as played out against the backdrop of a single patient. Thus, molecular epidemiology should not be construed as a descriptive science of those molecular defects present within a population, but rather the complex dynamics of selection between nongenetic, systemic, and environmental factors, and acquired somatic genetic defects, which arise at a surprisingly high rate among normal individuals. The resulting hybrid model incorporating multiple disciplines presents significant challenges for the individual contributing fields. Will molecular markers supplant diagnostic histopathology in clinical decision making? How should the value of precise and objective molecular analysis be weighed against the population variation and individual contexts in which they occur? Responsible clinical care will be the ultimate arbiter of these unresolved debates, and the best measure of future success.

An intriguing aspect of this disease is the latent phase—invisible to routine histopathological examination, but now detectable with specialized biomarkers. An extraordinarily high frequency of acquired silent mutations in histologically "normal" tissues, challenges the concept that initiation of carcinogenesis is an abnormal event, or even limited by mutational rates. It is very likely that those nongenetic events known to alter cancer risk act through their effect on such latent precancers. Reduction of risk, such as achieved by progestin exposure, leads to involution of latent precancers. Increase of cancer risk, such as caused by unopposed estrogen, leads to histological progression from latent to clinically diagnosable EIN disease. A rational conclusion is that many examples of endometrial cancer might be prevented by those interventions, which selectively destroy latent precancer cells. Correspondingly, the efficacy of such interventions might be measured in short order by direct observation of changes in the latent precan-cer prevalence before and after therapy. These hypotheses are easily formulated, can be tested experimentally in modestly sized populations during short periods of time, and could lead to bonafide cancer preventative strategies for this common disease.

0 0

Post a comment