Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment
Year: 2018
Type: preprint
Abstract: Driver mutations alter cells from normal to cancer through several evolutionary epochs: premalignancy, early malignancy, subclonal diversification, metastasis and resistance to therapy. Later stages of disease can be explored through analyzing multiple samples collected longitudinally, on or between successive treatments, and finally at time of autopsy. It is also possible to study earlier stages of cancer development through probabilistic reconstruction of developmental trajectories based on mutational information preserved in the genome. Here we present a suite of tools, called Phylogic N-Dimensional with Timing (PhylogicNDT), that statistically model phylogenetic and evolutionary trajectories based on mutation and copy-number data representing samples taken at single or multiple time points. PhylogicNDT can be used to infer: (i) the order of clonal driver events (including in pre-cancerous stages); (ii) subclonal populations of cells and their phylogenetic relationships; and (iii) cell population dynamics. We demonstrate the use of PhylogicNDT by applying it to whole-exome and whole-genome data of 498 lung adenocarcinoma samples (434 previously available and 64 of newly generated data). We identify significantly different progression trajectories across subtypes of lung adenocarcinoma ( EGFR mutant, KRAS mutant, fusion-driven and EGFR/KRAS wild type cancers). In addition, we study the progression of fusion-driven lung cancer in 21 patients by analyzing samples from multiple timepoints during treatment with 1st and next generation tyrosine kinase inhibitors. We characterize their subclonal diversification, dynamics, selection, and changes in mutational signatures and neoantigen load. This methodology will enable a systematic study of tumour initiation, progression and resistance across cancer types and therapies.
DOI: 10.1101/508127
Authors: Ignaty Leshchiner, Dimitri Livitz, Justin F. Gainor, Daniel Rosebrock, Oliver Spiro, Aina Martinez, Edmund Mroz, Jessica J. Lin, Chip Stewart, Jaegil Kim, Liudmila Elagina, Ivana Bozic, Mari Mino-Kenudson, Marguerite Rooney, Sai-Hong Ignatius Ou, Catherine J. Wu, James W. Rocco, Jeffrey A. Engelman, Alice T. Shaw, Gad Getz
Institutions: Broad Institute, Massachusetts General Hospital, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, University of Washington, University of California, Irvine, Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2906900419