How many mutations does it take to make a tumor?

I this issue of PNAS, Stoler and colleagues report that typical sporadic colorectal cancers on average contain at least 11,000 genomic alterations per cell (1). Furthermore, they report that the genomic instability responsible for generating this number of mutations starts very early in the neoplastic process and can be found in adenomatous polyps, which are known to be the precursors of cancer in the colon and rectum. Should this conclusion be emblazoned on the front page of the evening news, or does this serve to confirm and extend concepts that we already accept? To grasp the implications of this work, it will be helpful to briefly review the historical background of genomic instability and place this submission in that context. To do this, a series of questions must be posed. How does one measure mutations, and how can one quantitate heterogeneous alterations? Is it possible that tumors simply generate a very large number of alterations at genomic sequences that are irrelevant to issues of tumor development? If there are many mutations and only a few are biologically relevant, how does one determine whether mutations are important? Let’s see.