Genetic instability and clonal evolution: Implications for cancer prevention and cancer risk prediction.

Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006 CS07-02 Genetic instability is a hallmark of cancer that often precedes invasion and metastasis. This is important for three reasons. First, instability generates the genetic heterogeneity that fuels natural selection and neoplastic progression. Second, instability, coupled with natural selection, means that neoplasms vary genetically and epigenetically over both space and time. Thus, a biopsy may not be representative of the genetics of a neoplasm and will become less representative as a neoplasm changes over time. Third, instability can generate mutant clones that are resistant to future interventions, leading to response failures, resistance and relapse. The genetic diversity of a neoplasm is the result of the interaction of genetic instability generating new clones, and selective sweeps, that may homogenize the neoplasm by driving clones extinct. Thus, we do not expect diversity to increase monotonically with progression. We have shown in Barrett's esophagus that the degree of genetic diversity in a neoplasm predicts progression to malignancy. This suggests that selective sweeps are either uncommon late in progression or there is so much genetic instability late in progression that diversity is reestablished during, or shortly after, selective sweeps. This conclusion is supported by Shibata's work in colorectal cancer. Lesions that give a clone a fitness advantage and drive a clonal expansion make good biomarkers because they tend to generate large field effects that are easy to detect and because they are important in the evolutionary processes that drive progression. LOH in p16 (INK4A/CDKN2A) is associated with large clonal expansions in Barrett's esophagus. Biomarkers are typically evaluated using Cox models that assume hazard remains proportional and constant between risk groups. However, we have shown in Barrett's esophagus that p16 LOH has a time dependent hazard. It is unknown if this is due to changes in the neoplasm as clones evolve or if the hazard of p16 LOH depends on what other lesions hitchhike on the p16 clonal expansion. LOH in p53 (TP53), aneuploidy and tetraploidy tend to develop late in Barrett's progression and are associated with genetic instability. One might worry that they would be associated with the evolution of clones that are resistant to an intervention, and there is evidence that p53 mutant clones tend to survive photodynamic therapy. To our surprise, we found that NSAIDs, rather than failing in patients with p53 LOH and ploidy abnormalities, are actually more effective at preventing esophageal adenocarcinoma in these high risk groups compared to patients with no p53 or ploidy lesion. Thus, we have examined the impact of genetic instability and clonal evolution on progression, biomarker development and cancer prevention. All of these results will have to be tested in independent cohorts before they can be translated into clinical practice. Evolutionary analyses are helping us to understand progression, opening up new questions in cancer biology and, in the future, should become a central part of the study, treatment, and prevention of cancer.