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- Title
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.
- Authors
Koji Mochinaga; Tomoshi Tsuchiya; Toshiya Nagasaki; Junichi Arai; Tetsuro Tominaga; Naoya Yamasaki; Keitaro Matsumoto; Takuro Miyazaki; Atsushi Nanashima; Tomayoshi Hayashi; Kazuhiro Tsukamoto; Takeshi Nagayasu
- Abstract
The regulation of dihydropyrimidine dehydrogenase (DPD) in cancers with mutated epidermal growth factor receptor (EGFR) is unknown. In this study, the clinicopathologic analysis of 96 patients with non-small-cell lung cancer (NSCLC) and cell-based studies reveal high DPD expression in EGFR-mutated tumors. This finding should be taken into account in the design of a therapeutic strategy for the treatment of NSCLC. 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.
- Publication
Clinical Lung Cancer, 2014, Vol 15, Issue 2, p136
- ISSN
1525-7304
- Publication type
Article
- DOI
10.1016/j.cllc.2013.09.002