Highlights d Lung squamous cell carcinoma has a moderate level of intratumor genetic heterogeneity d Transcriptomic heterogeneity impacts cancer pathways, driving phenotypic heterogeneity d Neo-epitope burden negatively correlates with immune infiltration d Non-genetic heterogeneity influences tumor evolutionary dynamics

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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Impacts of genetic and nongenetic intratumor heterogeneity (ITH) on tumor phenotypes and evolvability remain debated. We analyzed ITH in lung squamous cell carcinoma at the levels of genome, transcriptome, tumor-immune interactions, and histopathologic characteristics by multiregion bulk and single-cell sequencing. Genomic heterogeneity alone was a weak indicator of intratumor nongenetic heterogeneity at immune and transcriptomic levels that impacted multiple cancer-related pathways, including those related to proliferation and inflammation, which in turn contributed to intratumor regional differences in histopathology and subtype classification. Tumor subclones had substantial differences in proliferation score, suggestive of non-neutral clonal dynamics. Proliferation and other cancer-related pathways also showed intratumor regional differences, sometimes even within the same subclones. Neoepitope burden negatively correlated with immune infiltration, indicating immune-mediated purifying selection on somatic mutations. Taken together, our observations suggest that nongenetic heterogeneity is a major determinant of heterogeneity in histopathologic characteristics and impacts evolutionary dynamics in lung cancer. Note: This abstract was not presented at the conference. Citation Format: Anchal Sharma, Elise Merritt, Xiaoju Hu, Angelique Cruz, Jyoti Malhotra, Greogory Riedlinger, Subhajyoti De. Impact of nongenetic intratumor heterogeneity on phenotypic characteristics and ongoing evolutionary dynamics in lung tumors [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B38.