title: Reconstructing metastatic seeding patterns of human cancers.
abstract: Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications. Genome-wide sequencing data has enabled modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumour samples at unprecedented depth. However, existing methods are not designed to infer metastatic seeding patterns. Here we develop a tool, called Treeomics, to reconstruct the phylogeny of metastases and map subclones to their anatomic locations. Treeomics infers comprehensive seeding patterns for pancreatic, ovarian, and prostate cancers. Moreover, Treeomics correctly disambiguates true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumour heterogeneity among distinct samples. In silico benchmarking on simulated tumour phylogenies across a wide range of sample purities (15-95%) and sequencing depths (25-800 × ) demonstrates the accuracy of Treeomics compared with existing methods.
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|IST (Institute of Science and Technology) Austria, Klosterneuburg 3400, Austria.
authors.forename: Johannes G
authors.identifier: 0000-0002-0170-7353
authors.initials: JG
authors.lastname: Reiter
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Alvin P
authors.initials: AP
authors.lastname: Makohon-Moore
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Jeffrey M
authors.identifier: 0000-0002-6363-2203
authors.initials: JM
authors.lastname: Gerold
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.affiliation: IST (Institute of Science and Technology) Austria, Klosterneuburg 3400, Austria.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chatterjee
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Christine A
authors.identifier: 0000-0002-4672-3023
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|The Ludwig Center and Howard Hughes Medical Institute at The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
mesh_terms: D001499:Bayes Theorem; D019985:Benchmarking; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010802:Phylogeny; D011471:Prostatic Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D040901:Proteomics / Q000379:methods*
chemical_list: D004273:DNA, Neoplasm