Fig. 2.

—Flowchart of the hypothesis testing of tumors as evolutionary islands. Rejection of hypotheses #1 and #2 might lead to the validation of hypothesis #3. Confirmation of hypothesis #1 does not necessarily reject hypothesis #2 because tumor heterogeneity patterns could still result from peculiar relationships between cancer cells and tumor sites and the degree of physical distance between anatomical sites. Tumor heterogeneity can be measured in numbers of cell or clone types, distinct molecular signatures, and average heterozygosity across sites, and standard genetic diversity in tumors. Ultimately, all three hypotheses may be true, depending on the cancer type and the number of tumor sites in a patient.