Featured Articles

Overview of the simulation framework and the genomic data analysis pipeline.

Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. read more...

(a) After initiation, a tumor grows predominantly as a single expansion populated by numerous heterogeneous subclones. ITH results from private alterations (colored arrowheads) that continuously accumulate owing to replication errors. In addition to public alterations present in the first transformed cell, private alterations acquired early persist and become pervasive in the final tumor although remaining non-dominant (colored segments). Late-arising alterations are only present in small regions of the tumor.

(b) In the Big Bang model, the pervasiveness of private alterations depends on when the alteration occurs during growth, rather than on selection for that alteration. The schematic illustrates how early private alterations, despite remaining non-dominant, are pervasive within the tumor (for example, red and yellow) and can be found in distant regions, thus appearing variegated (for example, red). This is owing to aberrant subclone mixing in the primordial tumor, followed by scattering during expansion. Late alterations are restricted to small regions (for example, black, pink, gray) and are essentially undetectable by conventional bulk genomic profiling. Distance from the dashed vertical axis corresponds to increasingly late onset for alterations. Dashed boxes represent sampled regions.

(c) We sampled an average of 23 individual tumor glands (<10,000 cells) from distant regions (~0.5 cm3 in size) and bulk (left and right) samples. Samples were profiled using several genomic techniques, including copy number analysis, whole-exome and targeted sequencing, neutral methylation tag sequencing and FISH, providing a panoramic view of genomic alterations throughout the tumor on multiple spatial scales.

Figure 1. The Big Bang model of tumor growth.