Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian cancer
- Abstract:
- Abstract Intra-tumor genetic heterogeneity is the result of ongoing evolutionary change within each cancer. The expansion of genetically distinct sub-clonal populations may explain the emergence of drug resistance and if so would have prognostic and predictive utility. However, methods for objectively quantifying tumor heterogeneity have been missing and are particularly difficult to establish in cancers where predominant copy number variation prevents accurate phylogenetic reconstruction because of horizontal dependencies caused by long and cascading genomic rearrangements. To address these challenges we have developed MEDICC, a method for phylogenetic reconstruction and heterogeneity quantification, which determines optimal phasing of major and minor alleles, computes evolutionary distances between samples, and reconstructs ancestral genomes. Rigorous simulations and an extensive clinical study show the power of our method, which outperforms state-of-the-art competitors in reconstruction accuracy and additionally allows unbiased numerical quantification of tumor heterogeneity. Using MEDICC we investigated the relationship between tumor heterogeneity and patient outcome in high-grade serous ovarian cancer. We found that tumor heterogeneity in this cancer is driven by ongoing clonal evolution with fully branched evolutionary trajectories that do not have clock-like evolutionary rates. Quantitative measures of clonal expansion and temporal heterogeneity were the strongest predictors of progression-free survival. We show in 2 patients that clonal expansion of a minor subclone that was present prior to chemotherapy led to clinical relapse. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL05-03. Citation Format: Florian M. Markowetz. Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL05-03.
- Authors:
- FM Markowetz
- Journal:
- Molecular Cancer Therapeutics
- Citation info:
- 12(11_Supplement):pl05-03-pl05-03
- Publication date:
- 1st Nov 2013
- Full text
- DOI