Figure 2. Linear and branched evolution of cancer.

Panel A. The linear model of disease has dominated medical thinking about early detection for more than a century. In its recent versions, it has postulated that a slow, gradual linear occurrence of molecular abnormalities (1, 2, 3, 4) cause changes in tissues (A, B, C, D) before the onset of cancer. This model predicts that interrupting any event (e.g., B) in the linear pathway will prevent progression. Panel B. Recent advances in genome technologies have reported that cancers arise by “branched evolution”. In some cases, such as in BE, an early branch leads to a state in which the esophageal metaplasia can remain stable for prolong periods of time even though it has some genomic alterations (B). However, in other BE, progression is branched. In this case inhibiting one step (e.g., E) will not necessarily block progression, which can proceed through C→D.