Reconstructing subclonal composition and evolution from whole genome sequencing of tumors

Tumors contain multiple, genetically diverse subclonal populations of cells that have evolved from a single progenitor population through successive waves of expansion and selection [1-3]. Reconstructing their evolutionary histories can help identify characteristic driver mutations associated with cancer development and progression [4, 5]; and can provide insight into how tumors might respond to treatment [6, 7]. In some cases, it is possible to genotype the subpopulations present in a tumor, while reconstructing its history, using the population frequencies of mutations that distinguish these subclonal populations [2, 8-21]. Increasingly, tumors are being characterized using whole genome sequencing (WGS) of bulk tumor samples [22] and few automated methods exist to reliably perform this reconstruction on the basis of these data. Subclonal reconstruction algorithms attempt to infer the population structure of heterogeneous tumors based on the measured variant allelic frequency (VAF) of their somatic mutations.