title: TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data.
abstract: The evolution of cancer genomes within a single tumor creates mixed cell populations with divergent somatic mutational landscapes. Inference of tumor subpopulations has been disproportionately focused on the assessment of somatic point mutations, whereas computational methods targeting evolutionary dynamics of copy number alterations (CNA) and loss of heterozygosity (LOH) in whole-genome sequencing data remain underdeveloped. We present a novel probabilistic model, TITAN, to infer CNA and LOH events while accounting for mixtures of cell populations, thereby estimating the proportion of cells harboring each event. We evaluate TITAN on idealized mixtures, simulating clonal populations from whole-genome sequences taken from genomically heterogeneous ovarian tumor sites collected from the same patient. In addition, we show in 23 whole genomes of breast tumors that the inference of CNA and LOH using TITAN critically informs population structure and the nature of the evolving cancer genome. Finally, we experimentally validated subclonal predictions using fluorescence in situ hybridization (FISH) and single-cell sequencing from an ovarian cancer patient sample, thereby recapitulating the key modeling assumptions of TITAN.
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada; sshah@bccrc.ca.
authors: Gavin
authors: G
authors: Ha
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada;
authors: Andrew
authors: A
authors: Roth
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Jaswinder
authors: J
authors: Khattra
authors: Centre for Translational and Applied Genomics, Vancouver, BC V5Z 4E6, Canada;
authors: Julie
authors: J
authors: Ho
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Damian
authors: D
authors: Yap
authors: Centre for Translational and Applied Genomics, Vancouver, BC V5Z 4E6, Canada;
authors: Leah M
authors: LM
authors: Prentice
authors: Centre for Translational and Applied Genomics, Vancouver, BC V5Z 4E6, Canada;
authors: Nataliya
authors: N
authors: Melnyk
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada;
authors: Andrew
authors: A
authors: McPherson
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Ali
authors: A
authors: Bashashati
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Emma
authors: E
authors: Laks
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Justina
authors: J
authors: Biele
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Computer Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;
authors: Jiarui
authors: J
authors: Ding
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Alan
authors: A
authors: Le
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Jamie
authors: J
authors: Rosner
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Karey
authors: K
authors: Shumansky
authors: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada;
authors: Marco A
authors: MA
authors: Marra
authors: Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC V6H 3Z6, Canada;
authors: C Blake
authors: CB
authors: Gilks
authors: Centre for Translational and Applied Genomics, Vancouver, BC V5Z 4E6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada;
authors: David G
authors: DG
authors: Huntsman
authors: Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors: Jessica N
authors: JN
authors: McAlpine
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada;
authors: Samuel
authors: S
authors: Aparicio
authors: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Computer Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; sshah@bccrc.ca.
authors: Sohrab P
authors: SP
authors: Shah
mesh_terms: D000465:Algorithms; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology / Q000379:methods*; D056915:DNA Copy Number Variations; D005260:Female; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D019656:Loss of Heterozygosity; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods; D064726:Triple Negative Breast Neoplasms / Q000235:genetics