The reduced expression and aberrant methylation of p16(INK4a) in chromate workers with lung cancer.
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.
Kondo
Kazuya
K
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
Takahashi
Yuji
Y
Hirose
Yukiko
Y
Nagao
Taeko
T
Tsuyuguchi
Masaru
M
Hashimoto
Masato
M
Ochiai
Atsushi
A
Monden
Yasumasa
Y
Tangoku
Akira
A
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
D002840:Chromates; D019941:Cyclin-Dependent Kinase Inhibitor p16; D013447:Sulfites; D002857:Chromium; D004247:DNA; C009279:sodium bisulfite