1. High expression of dihydropyrimidine dehydrogenase in lung adenocarcinoma is associated with mutations in epidermal growth factor receptor: implications for the treatment of non--small-cell lung cancer using 5-fluorouracil.
- Author
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Mochinaga K, Tsuchiya T, Nagasaki T, Arai J, Tominaga T, Yamasaki N, Matsumoto K, Miyazaki T, Nanashima A, Hayashi T, Tsukamoto K, and Nagayasu T
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma metabolism, Adenocarcinoma pathology, Aged, Antimetabolites, Antineoplastic therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Dihydrouracil Dehydrogenase (NADP) metabolism, ErbB Receptors metabolism, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, Male, Neoplasm Staging, Polymerase Chain Reaction, Prognosis, Thymidylate Synthase genetics, Thymidylate Synthase metabolism, Carcinoma, Non-Small-Cell Lung genetics, Dihydrouracil Dehydrogenase (NADP) genetics, ErbB Receptors genetics, Fluorouracil therapeutic use, Lung Neoplasms genetics, Mutation genetics
- Abstract
Background: It has been shown that 5-fluorouracil (5-FU) sensitivity in patients with non-small-cell lung cancer (NSCLC) is associated with epidermal growth factor receptor (EGFR) mutation status. However, the relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status is unknown. Here, we focus on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status., Patients and Methods: EGFR mutations and messenger RNA (mRNA) levels of DPD and thymidylate synthase (TS) were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. In addition, relationships between EGFR mutation status and the immunohistochemical expression of DPD and TS in 49 patients with primary NSCLC who were treated with a 5-FU derivative of S-1 postoperatively were examined. Correlations among clinicopathologic factors were evaluated. The effect of epidermal growth factor on DPD expression was also investigated in vitro in various cell lines., Results: Adenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P < .05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers. DPD immunopositive cases were correlated with EGFR mutation status (P < .003). The prognoses of wild-type EGFR and mutated EGFR populations were similarly favorable with postoperative S-1 treatment, which overcomes the problem of 5-FU degradation in mutated EGFR. In vitro, EGFR-mutated cell lines showed high DPD mRNA and protein expression., Conclusion: High DPD expression was shown to be correlated with EGFR mutation in adenocarcinoma cells and tissues. Clinicians should take this finding into consideration when using 5-FU to treat patients with NSCLC., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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