On the nature of genetic changes required for the development of esophageal cancer.

It is clear that genetic mutations are necessary for the development of cancer, but the exact number required is not clear, with estimates ranging from one critical hit (e.g., p53) to dozens or perhaps even hundreds of expression changes (by microarray analysis) or chromosomal aberrations. We have used a mathematical model to estimate the critical number of mutations required for the development of esophageal cancer (EC) and to test for the likelihood of an EC major susceptibility gene. Our results suggest that six or seven mutations are required for the development of EC and that there is no evidence of a major susceptibility gene. This does not exclude the possibility that gene-environment interactions may not confer susceptibility or risk. The gradual accumulation of aberrant gene function also can explain the progression of pathologic states seen in the esophagus, from early dysplasia through mild to severe dysplasia and, finally, to cancer, as illustrated in our model.