title: The reduced expression and aberrant methylation of p16(INK4a) in chromate workers with lung cancer.
abstract: OBJECTIVE
  It is known that chromium is one of the important inhaled carcinogens that cause lung cancer. Our previous studies revealed a variety of genetic changes in lung cancers from chromate-exposed workers (chromate lung cancer). However, the epigenetic effects of chromium are not understood.
  
  
  METHODS
  We investigated the methylation of the p16 gene using a methylation-specific PCR method in 30 chromate lung cancers and 38 non-chromate lung cancers, and the expression of the p16 protein using immunohistochemistry in 25 chromate lung cancers.
  
  
  RESULTS
  Ten (33%) chromate lung cancers showed methylation of the p16 promoter region. On the other hand, 10 (26%) of the non-chromate lung cancers also showed it. The frequency of p16 methylation in non-chromate lung cancer was 0%, 33% and 30% for low (< or =600), moderate (<600, >1000) and high (> or =1000) Brinkman indexes, respectively. However, the frequency of p16 methylation in chromate lung cancer was constant, irrespective of the Brinkman index. In chromate lung cancer, patients with chromate exposure of less than 15 years never had p16 methylation, while 40% (> or =25 years) or 43% (> or =15, <25 years) of patients with chromate exposure of more than 15 years did. In chromate lung cancer, chromate exposure, not smoking, mainly influenced the p16 methylation. Most of the chromate lung cancers with p16 methylation (85.7%) showed repression of the p16 protein.
  
  
  CONCLUSIONS
  We speculate that not only genetic but also epigenetic alterations are involved in the carcinogenesis due to chromium.
authors.affiliation: Department of Oncological and Regenerative Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, 3-chome, Kuramoto-cho, Tokushima City 770-8503, Japan. kondo@clin.med.tokushima-u.ac.jp
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kondo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hirose
authors.forename: Taeko
authors.initials: T
authors.lastname: Nagao
authors.forename: Masaru
authors.initials: M
authors.lastname: Tsuyuguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Monden
authors.forename: Akira
authors.initials: A
authors.lastname: Tangoku
mesh_terms: D000328:Adult; D000368:Aged; D002840:Chromates / Q000633:toxicity*; D002857:Chromium / Q000737:chemistry; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D013447:Sulfites / Q000494:pharmacology
chemical_list: D002840:Chromates; D019941:Cyclin-Dependent Kinase Inhibitor p16; D013447:Sulfites; D002857:Chromium; D004247:DNA; C009279:sodium bisulfite