title: BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data.
abstract: Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients' primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community (https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html).
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA weizhu365@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kuziora
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Creasy
authors.affiliation: Oncology iMed, AstraZeneca, Waltham, MA 02451, USA.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Morehouse
authors.affiliation: Clinical Biomarkers and Computational Biology, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Sebastian
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Oncology iMed, AstraZeneca, Waltham, MA 02451, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dry
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD 20878, USA weizhu365@gmail.com.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
mesh_terms: D000465:Algorithms; D000782:Aneuploidy; D056915:DNA Copy Number Variations; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D012984:Software