Microbiome-TP53 Gene Interaction in Human Lung Cancer

Greathouse, K. L.; White, J. R.; Vargas, A. J.; Bliskovsky, V. V.; Beck, J. A.; von Muhlinen, N.; Polley, E. C.; Bowman, E. D.; Khan, M. A.; Robles, A. I.; Cooks, T.; Ryan, B. M.; Dzutsev, A. H.; Trinchieri, G.; Pineda, M. A.; Bilke, S.; Meltzer, P. S.; Hokenstad, A. N.; Stickrod, T. M.; Walther-Antonio, M. R.; Earl, J. P.; Mell, J. C.; Krol, J. E.; Balashov, S. V.; Bhat, A. S.; Ehrlich, G. D.; Valm, A.; Deming, C.; Conlan, S.; Oh, J.; Segre, J. A.; Harris, C. C.

doi:10.1101/273524

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bioRxiv · 10.1101/273524

Microbiome-TP53 Gene Interaction in Human Lung Cancer

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Abstract

BackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.\n\nResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).\n\nConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

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Greathouse, K. L., White, J. R., Vargas, A. J., Bliskovsky, V. V., Beck, J. A., von Muhlinen, N., Polley, E. C., Bowman, E. D., Khan, M. A., Robles, A. I., Cooks, T., Ryan, B. M., Dzutsev, A. H., Trinchieri, G., Pineda, M. A., Bilke, S., Meltzer, P. S., Hokenstad, A. N., Stickrod, T. M., Walther-Antonio, M. R., Earl, J. P., Mell, J. C., Krol, J. E., Balashov, S. V., Bhat, A. S., Ehrlich, G. D., Valm, A., Deming, C., Conlan, S., Oh, J., Segre, J. A., Harris, C. C.. 2018-02-28. Microbiome-TP53 Gene Interaction in Human Lung Cancer. https://doi.org/10.1101/273524

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