Inferring clonal evolution of tumors from single nucleotide somatic mutations

Wei Jiao, Shankar Vembu, Amit G Deshwar, Lincoln Stein, Quaid Morris
2014 BMC Bioinformatics  
High-throughput sequencing allows the detection and quantification of frequencies of somatic single nucleotide variants (SNV) in heterogeneous tumor cell populations. In some cases, the evolutionary history and population frequency of the subclonal lineages of tumor cells present in the sample can be reconstructed from these SNV frequency measurements. But automated methods to do this reconstruction are not available and the conditions under which reconstruction is possible have not been
more » ... ed. Results: We describe the conditions under which the evolutionary history can be uniquely reconstructed from SNV frequencies from single or multiple samples from the tumor population and we introduce a new statistical model, PhyloSub, that infers the phylogeny and genotype of the major subclonal lineages represented in the population of cancer cells. It uses a Bayesian nonparametric prior over trees that groups SNVs into major subclonal lineages and automatically estimates the number of lineages and their ancestry. We sample from the joint posterior distribution over trees to identify evolutionary histories and cell population frequencies that have the highest probability of generating the observed SNV frequency data. When multiple phylogenies are consistent with a given set of SNV frequencies, PhyloSub represents the uncertainty in the tumor phylogeny using a "partial order plot". Experiments on a simulated dataset and two real datasets comprising tumor samples from acute myeloid leukemia and chronic lymphocytic leukemia patients demonstrate that PhyloSub can infer both linear (or chain) and branching lineages and its inferences are in good agreement with ground truth, where it is available. Conclusions: PhyloSub can be applied to frequencies of any "binary" somatic mutation, including SNVs as well as small insertions and deletions. The PhyloSub and partial order plot software is available from https://github.com/ morrislab/phylosub/. frequencies of mutations that distinguish the subclonal populations [5] [6] [7] [8] [9] [10] [11] [12] [13] . Somatic mutations can be detected, and roughly quantified, using exome and whole genome sequencing of a sample from a bulk tumor [14] . However, recent attempts to reconstruct subclonal phylogenies have employed much deeper targeted sequencing [15] of tumor-associated single nucleotide variants (SNVs) to achieve higher accuracy in estimated SNV frequencies [9, 10, 16, 17] . These SNV frequencies were then used to partially reconstruct the evolutionary history of tumors based on a single [10, 16] or multiple [9] samples of same tumor. However, due to short read sequencing, the frequencies of different SNVs are measured independently, so linkage between the SNVs in subclones is unavailable and standard phylogenetic methodology can not be used to construct evolutionary histories (as done in [18] or [17] ). However, if one
doi:10.1186/1471-2105-15-35 pmid:24484323 pmcid:PMC3922638 fatcat:mdadr3njpbanvjkbcmq4gjidxu