title: Heme-related gene expression signatures of meat intakes in lung cancer tissues.
abstract: Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤ 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer.
authors.affiliation: Cancer Prevention Fellowship Program, Office of Preventive Oncology, Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health (NIH), DHHS, Bethesda, Maryland; Division of Cancer Epidemiology and Genetics, Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health (NIH), DHHS, Bethesda, Maryland.
authors.forename: Tram Kim
authors.initials: TK
authors.lastname: Lam
authors.forename: Melissa
authors.initials: M
authors.lastname: Rotunno
authors.forename: Brid M
authors.initials: BM
authors.lastname: Ryan
authors.forename: Angela C
authors.initials: AC
authors.lastname: Pesatori
authors.forename: Pier Alberto
authors.initials: PA
authors.lastname: Bertazzi
authors.forename: Margaret
authors.initials: M
authors.lastname: Spitz
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics*; D016022:Case-Control Studies; D004032:Diet; D004435:Eating; D005247:Feeding Behavior; D005260:Female; D020869:Gene Expression Profiling; D006418:Heme; D006801:Humans; D019266:Iron, Dietary / Q000009:adverse effects*; D050356:Lipid Metabolism / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008460:Meat / Q000009:adverse effects*; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D012306:Risk; D012307:Risk Factors; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D019266:Iron, Dietary; D006418:Heme
keywords: gene expression; heme-iron; lung cancer