title: NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.
abstract: BACKGROUND
  Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners.
  
  
  RESULTS
  Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%.
  
  
  CONCLUSIONS
  These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.
authors.affiliation: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany. pesch@ipa-dguv.de
authors.forename: Beate
authors.initials: B
authors.lastname: Pesch
authors.forename: Swaantje
authors.initials: S
authors.lastname: Casjens
authors.forename: Ingo
authors.initials: I
authors.lastname: Stricker
authors.forename: Daniela
authors.initials: D
authors.lastname: Westerwick
authors.forename: Dirk
authors.initials: D
authors.lastname: Taeger
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rabstein
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiethege
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Georg
authors.initials: G
authors.lastname: Johnen
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000139:chemically induced / Q000145:classification / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008906:Mining; D016273:Occupational Exposure / Q000009:adverse effects*; D051881:Receptor, Notch1 / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000139:chemically induced / Q000378:metabolism; D014501:Uranium / Q000633:toxicity*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014501:Uranium