Bubbletree: An Intuitive Visualization To Elucidate Tumoral Aneuploidy And Clonality In Somatic Mosaicism Using Copy Number Ratio And Allele Frequency

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PABackgroundTumors are characterized by properties of instability, heterogeneity, and significant oligoclonality. Elucidating these patterns of tumor clonal evolution is critical to our understanding of neoplastic development, which can ultimately improve diagnosis and treatment decisions in cancer therapy.MethodsBubbleTree is an intuitive tree-like graph used to simultaneously illustrate tumor cell prevalence, allele-specific copy number, and clonality in human tumor specimens. This method evaluates somatic copy number alterations (SCNAs) at the focal genomic segment level to determine allele-specific copy number and elucidate the clonal hierarchy within tumors. Further, BubbleTree can longitudinally track genetic alterations in clonality during tumor progression and/or recurrence. Two models, a Bayesian and finite mixture distribution-based method, were developed to automate the interpretation of the BubbleTree graph. Both whole genome and whole exome sequencing (WGS and WES, respectively) data from three case studies are presented using the BubbleTree method: paired primary tumors in the lung and ovary from a patient, matched primary and recurrent liver tumors from a hepatocellular carcinoma (HCC) patient, and matched primary liver and metastatic lung tumors in a second HCC patient.ResultsBubbleTree accurately identified both inherited and altered karyotypes, as well as their prevalence between primary and recurrent liver tumors in two HCC patients, which suggests that the recurrent HCC malignancy post orthotopic liver transplantation originated from the primary tumor, with novel subclonal expansion during metastasis. Furthermore, BubbleTree accurately reveals the dominant clone and instable subclones in the lung tumor of a patient with synchronous double malignancies; these results were validated by fluorescent in situ hybridization.ConclusionsOur model is robust for both WGS and WES data, with consistency demonstrated on both data types from the same tumor biopsy. The BubbleTree diagram and model presented here is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in tumors. Further, this tool is a free R package available for download at Bioconductor.Citation Format: Wei Zhu, Mike Kuziora, Chris Morehouse, Tianwei Zhang, Yinong Sebastian, Zheng Liu, Dong Shen, Jiaqi Huang, Zhengwei Dong, Yi Gu, Feng Xue, Liyan Jiang, Yihong Yao, Brandon W. Higgs. BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality in somatic mosaicism using copy number ratio and allele frequency. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4851. doi:10.1158/1538-7445.AM2015-4851