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).

Examining the contribution of smoking and HPV towards the etiology of oral cavity squamous cell carcinoma using high-throughput sequencing: A prospective observational study

“…To gain a perspective of the subclonal architecture of the OCSCC tumors in this study, the recently published BubbleTree [ 20 ] prediction analysis was applied to the tumor DNA dataset ( S4 – S6 Figs). The analysis uses tumor beta allele frequencies at germline heterozygous loci and somatic copy number alterations to predict the prevalence of (sub)tumors.…”

“…Circular binary segmentation was performed using the DNAcopy library from BioConductor [ 19 ]. Beta allele frequencies at germline heterozygous loci in tumor samples from MuTect output and copy number alterations identified from VarScan2 were used as input for predicting tumor and subclonal purity and ploidy using the BubbleTree visualization tool from BioConductor [ 20 ].…”

The subclonal structure and genomic evolution of oral squamous cell carcinoma revealed by ultra-deep sequencing

“…In contrast, the cancers of patient 2 and 4 seem to be very homogenous as their biopsies share the same mutations with no evidence of intra-tumor heterogeneity. Additionally, we used the recently published tool BubbleTree [17] to run an independent heterogeneity analysis using copy number data from germline variants and somatic copy number aberrations obtained from the exome sequencing. The results verify our estimated tumor contents and the existence of the most prominent subclones we find, supporting our phylogenetic analysis.…”

Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

“…Bubble Tree analysis 16 was performed to estimate tumor purity, ploidy and clonality, inferred from exome sequencing data ( Supplementary Figs S2–S21 ). The tumor purity of the samples, based on these analyses, ranges between 0.24–0.95 ( Supplementary Table S2 ).…”