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bioRxiv · 10.1101/698845

Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors

Sharma, A.·Merritt, E.·Cruz, A.·Jiang, C.·Sarkodie, H.·Zhou, Z.·Malhotra, J.·Riedlinger, G. M.·De, S.
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Abstract

Impacts of genetic and non-genetic intra-tumor heterogeneity (ITH) on tumor phenotypes and evolvability remain debated. We analyzed ITH in lung squamous cell carcinoma (LUSC) at the levels of genome, transcriptome, tumor-immune interactions, and histopathological characteristics by multi-region profiling and using single-cell sequencing data. Overall, in LUSC genomic heterogeneity alone was a weak indicator of intra-tumor non-genetic heterogeneity at immune and transcriptomic levels that impacted multiple cancer-related pathways including those related to proliferation and inflammation, which in turn contributed to intra-tumor regional differences in histopathology and subtype classification. Genome, transcriptome, and immune-level heterogeneity influenced different aspects of tumor evolution. Tumor subclones had substantial differences in proliferation score, suggestive of non-neutral clonal dynamics. Scores for proliferation and other cancer-related pathways also showed intra-tumor regional differences, sometimes even within the same subclones. Neo-epitope burden negatively correlated with immune infiltration, indicating potential immune-mediated purifying selection on acquired mutations in these tumors. Taken together, our observations suggest that non-genetic heterogeneity is a major determinant of heterogeneity in histopathological characteristics and impacts evolutionary dynamics in lung cancer.

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Sharma, A., Merritt, E., Cruz, A., Jiang, C., Sarkodie, H., Zhou, Z., Malhotra, J., Riedlinger, G. M., De, S.. 2019-07-11. Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors. https://doi.org/10.1101/698845

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