Significant Correlation of Nitric Oxide Synthase Activity and p53 Gene Mutation in Stage I Lung Adenocarcinoma

• Published in: Cancer science Vol. 89; no. 7; pp. 696 - 702
• Main Authors: Fujimoto, Hisao, Sasaki, Ji‐ichiro, Matsumoto, Mitsuhiro, Suga, Moritaka, Ando, Yukio, Iggo, Richard, Tada, Mitsuhiro, Saya, Hideyuki, Ando, Masayuki
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.1998; John Wiley & Sons, Inc
• Subjects: Adenocarcinoma; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Aged; Carcinogenesis; Carcinogens; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA damage; Female; Genes, p53; Humans; key words; Lung adenocarcinoma; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lungs; Male; Middle Aged; Mutation; Nitric oxide; Nitric Oxide - physiology; Nitric oxide synthase; Nitric Oxide Synthase - metabolism; Nucleotide sequence; p53; p53 Protein; Point mutation; Sequence analysis; Transversion; Tumor suppressor genes; Yeast functional assay
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1998.tb03273.x

Nitric oxide (NO) and its derivatives can directly cause DNA damage and mutation in vitro and may play a role in the multistage carcinogenic process. It has been reported that NO induces mutation in the p53 tumor suppressor gene; we therefore analyzed the relationship between NO synthase 9 activity and p53 gene status in early‐stage lung adenocarcinoma. Surgical samples were classified into two categories: 14 lung adenocarcinomas with high NOS activity (>25 pmol/min/g tissue, category A), and 16 with low NOS activity (<25 pmol/min/g tissue, category B). A yeast functional assay for p53 mutations disclosed a red colony that corresponded to a mutation in the p53 gene in 8 cases (57.1%) in category A and 3 cases (18.8%) in category B, the frequency being significantly higher in the former (P<0.05). A p53 DNA sequence analysis revealed that 5 of the 8 p53 mutation‐positive samples in category A had a G:C‐to‐T:A transversion, which is reported to be a major target of NO. The mechanism of carcinogenesis of adenocarcinoma is not fully understood, but these results suggest that an excess of endogenously formed NO may induce a p53 gene mutation containing mainly G:C‐to‐T:A transversion in the early stage of lung adenocarcinoma. Our results suggest that NO has potential mutagenic and carcinogenic activity, and may play important roles in human lung adenocarcinoma.