Abstract 2748: Gene expression signatures of meat intake in lung cancer tissues
Authors: Melissa Rotunno, Tram K. Lam, Neil E. Caporaso, Maria Teresa Landi
Journal: Cancer Research (2011)

Abstract Epidemiologic studies, including the Environment and Genetics in Lung cancer Etiology (EAGLE), have reported increased consumption of red and processed meats to be associated with higher risk of lung cancer. Several plausible molecular mechanisms, including endogenous heme-iron exposure, may link meat with lung cancer. No study has investigated the mechanisms underlying this association using whole genome expression. We used Affymetrix HG U133A chip to measure genome-wide expression differences by meat intake in fresh frozen tumor and non-involved lung tissues of 72 adeonocarcinoma patients from the EAGLE study. EAGLE is a large population-based case-control study of 2100 cases and 2120 controls living in the North of Italy, a region with high consumption of fresh red and processed meats. Among individuals with gene expression data, we compared the gene expression profile between individuals consuming high-versus-low meat intake, based on the distribution of the entire EAGLE population, using unadjusted two samples t-test and sex, age, and smoking adjusted ANOVA test. We found that gene expression profile in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above and below the median intake of fresh red meats among all stage patients (269 gene-probes, maximum False Discovery Rate (FDR) = 0.12, based on a single gene-probe p-value threshold of 0.001), and even more strongly among early stage patients (341 gene-probes, FDR = 0.10). We further studied the identified gene signature by means of a) manually curate literature search, b) cross comparison of several pathway analysis tools, and c) investigation of transcription factor master regulators. We identified genes involved in molecular functions that may play a key role in meat-related carcinogenesis, including heme binding transport activity (CYP4A11, TPO, CYP2C8, NENF, CYP3443, SLC1A2, SLC5A7, SLC30A6, HGR, HPX, HFE), transcription regulator activity (ELK1, FOXB1, SOX10, SOX21, SOX5, PAX3, MAF, MAP2K7), and folate-related activity (MTHFR). A replication study of the candidate gene expression signature identified in EAGLE, using Real-Time Quantitative PCR, is ongoing in additional 50 lung cancer cases from an independent population of high meat consumers. For the confirmed genes, we plan to investigate whether common genetic variants in these genes modify meat-related lung cancer risk associations using Genome Wide Association data in all 4000 EAGLE subjects. In conclusion, we identified candidate genes belonging to several molecular pathways whose expression differentiates between high-versus-low consumers of fresh red meats and consequently may contribute to the etiology of meat-related lung carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2748. doi:10.1158/1538-7445.AM2011-2748