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).
Highlights
A common characteristic shared among malignant cancerous cells is impaired DNA repair, which in turn leads to genome instability [1,2,3,4,5]
We found no significant difference between the double malignancy (DM)Lung WGS and whole exome sequencing (WES) data (Figure 6C)
We evaluated the generalizability of BubbleTree for performance on both WES and WGS data types, as there is a clear difference in granularity in coverage between these two sequencing data types
Summary
A common characteristic shared among malignant cancerous cells is impaired DNA repair, which in turn leads to genome instability [1,2,3,4,5]. As a result of this instability, tumor cells progressively acquire additional DNA aberrations throughout the lifetime of a tumor. Analogous to Darwinian natural selection, cancer progression can be regarded as a process of clonal expansion [6,7]. The resulting tumor comprises a heterogeneous mixture of genetically distinct cell populations. This heterogeneity enables a tumor to adapt to differing selective pressures such as drug therapy to prolong tumor survival [12], it is of great importance to understanding the inherent tumor clonal structure
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