Journal Article

Interaction between the microbiome and TP53 in human lung cancer

Greathouse, K. Leigh, Trinchieri, Giorgio, Cooks, Tomer, Stickrod, Tricia M., Meltzer, Paul S., Harris, Curtis C., Vargas, Ashely J., Bhat, Archana S., Deming, Clayton, Robles, Ana I., Mell, Joshua C., Ryan, Bríd M., Dzutsev, Amiran H., Segre, Julie A., Conlan, Sean, Khan, Mohammed A., Ehrlich, Garth D., Oh, Julia, Polley, Eric C., Valm, Alex, Walther-Antonio, Marina R., Balashov, Sergey V., Pineda, Marbin A., Beck, Jessica A., Hokenstad, Alexis N., Earl, Joshua P., Padgett, Noah, White, James R., Bliskovsky, Valery V., Bilke, Sven, Krol, Jaroslaw E., von Muhlinen, Natalia, Bowman, Elise D.

2018

Overview

Background Lung 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 hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. Results Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax , exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. Conclusions The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Acidovorax / adenocarcinoma / Adult / Aged / Animal Genetics and Genomics / Bacteria / Bacterial infections / Biodiversity / Bioinformatics / Biomarkers / Biomedical and Life Sciences / Cancer therapies / Carcinogenesis / Chronic obstructive pulmonary disease / Cigarette smoke / Cigarettes / Colorectal cancer / Comamonadaceae - classification / Comamonadaceae - physiology / Cystic fibrosis / epithelium / Evolutionary Biology / Female / fluorescence / Fluorescence in situ hybridization / genes / Genomes / Human Genetics / Humans / hybridization / Immunotherapy / Inflammation / Life Sciences / Lung cancer / Lung carcinoma / lung neoplasms / Lung Neoplasms - genetics / Lung Neoplasms - microbiology / lungs / Male / Medical diagnosis / Microbial Genetics and Genomics / Microbiome / Microbiomes / Microbiomes and Metagenomics / Microbiota / Microbiota - genetics / microorganisms / Middle Aged / Mutation / Mutation - genetics / Neoplasms, Squamous Cell - genetics / Neoplasms, Squamous Cell - microbiology / p53 Protein / Plant Genetics and Genomics / Proteobacteria - metabolism / Reproducibility of Results / ribosomal RNA / risk factors / rRNA 16S / sequence analysis / smoke / Smokers / Smoking / species diversity / Squamous cell carcinoma / Tobacco smoke / TP53 / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors