@article {Rubanova260471, author = {Yulia Rubanova and Ruian Shi and Roujia Li and Jeff Wintersinger and Nil Sahin and Amit Deshwar and Quaid Morris and PCAWG Evolution and Heterogeneity Working Group and PCAWG network}, title = {TrackSig: reconstructing evolutionary trajectories of mutations in cancer}, elocation-id = {260471}, year = {2018}, doi = {10.1101/260471}, publisher = {Cold Spring Harbor Laboratory}, abstract = {We present a new method, TrackSig, to estimate the evolutionary trajectories of signatures of somatic mutational processes. TrackSig uses cancer cell fraction (CCF) corrected by copy number to infer an approximate order in which the somatic mutations accumulate. TrackSig segments mutation ordering by CCF and fits signature exposures (activities) as a piece-wise constant function of the mutation ordering. TrackSig uses optimal segmentation to find the points of change in signature activities.We assess TrackSig{\textquoteright}s reconstruction accuracy using simulations. We find 2\% median activity error on simulations with one to three change-points. The size and the direction of the signature change is consistent in 83\% and 95\% of cases respectively. There were an average of 0.02 missed change-points and 0.12 false positive change-points per sample. We provide a framework to estimate signature exposure trajectories across CCF scale as well as the way to determine active signatures. The code is available at https://github.com/YuliaRubanova/TrackSig.}, URL = {https://www.biorxiv.org/content/early/2018/11/15/260471}, eprint = {https://www.biorxiv.org/content/early/2018/11/15/260471.full.pdf}, journal = {bioRxiv} }