@article {Sharma698845, author = {Anchal Sharma and Elise Merritt and Angelique Cruz and Chuan Jiang and Halle Sarkodie and Zhan Zhou and Jyoti Malhotra and Gregory M Riedlinger and Subhajyoti De}, title = {Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors}, elocation-id = {698845}, year = {2019}, doi = {10.1101/698845}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Impact of genetic and non-genetic intra-tumor heterogeneity (ITH) on tumor phenotypes and evolvability remain debated. We analyze ITH in lung squamous cell carcinoma at the levels of genome, transcriptome, tumor-immune interactions, and histopathological characteristics by multi-region profiling. Genetic heterogeneity underestimates the extent of transcriptional heterogeneity, which impacts multiple cancer-related pathways, leading up to regional differences in tumor subtype, multi-drug resistance, and proliferative potential. Using meta-ITH, a framework developed here, we note that non-genetic heterogeneity correctly predicts ITH in histopathological characteristics, which was not effectively captured at any one level. Genome, transcriptome and immune-level heterogeneity reveal different selection pressures on tumors. Detectable subclones often show differences in estimated growth rates, indicating non-neutral tumor evolution. Neo-epitope burden negatively correlates with immune infiltration, indicating further immune-mediated purifying selection on genetic variations in these tumors. Taken together, non-genetic heterogeneity is a dominant predictor of phenotypic heterogeneity and reveals ongoing evolutionary dynamics in lung cancer.}, URL = {https://www.biorxiv.org/content/early/2019/07/11/698845}, eprint = {https://www.biorxiv.org/content/early/2019/07/11/698845.full.pdf}, journal = {bioRxiv} }