Figure 5.

Accumulation of genomic alterations and emergence of resistance. Cancer begins with a single genomic alteration in a cancer-related gene, which provides a selective growth advantage that allows the cell with the original “clonal mutation” (also known as the “truncal mutation”) to grow and divide more quickly than neighboring healthy cells. Over time, additional genomic alterations accumulate in the DNA of these cancerous cells, leading to both linear and branched evolution from the original clonal population. This leads to a tumor comprised of various subclones, all of which share the original truncal mutation but also feature additional, unique mutations (known as “private mutations”). Administration of an efficacious treatment will typically eliminate many cells in the tumor, resulting in a reduction in tumor burden and clinical remission; however, certain subclones already harboring resistance mutations will often survive treatment at clinically undetectable levels and subsequently expand in the absence of competition. In time, this leads to the clinical observation of recurrence.