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.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Mochinaga
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Arai
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamasaki
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nanashima
authors.affiliation: Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: nagayasu@nagasaki-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; C512478:EGFR protein, human; D066246:ErbB Receptors; D005472:Fluorouracil
keywords: Adenocarcinoma in situ; Dihydropyrimidine dehydrogenase; S-1; epidermal growth factor receptor mutation; epidermal growth factor receptor tyrosine kinase inhibitor