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

Clin Lung Cancer. 2014 Mar;15(2):136-144.e4. doi: 10.1016/j.cllc.2013.09.002. Epub 2013 Nov 14.

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.

Keywords: Adenocarcinoma in situ; Dihydropyrimidine dehydrogenase; S-1; epidermal growth factor receptor mutation; epidermal growth factor receptor tyrosine kinase inhibitor.

MeSH terms

  • 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 / genetics*
  • 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) / genetics*
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Female
  • Fluorouracil / therapeutic use*
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mutation / genetics*
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Prognosis
  • Thymidylate Synthase / genetics
  • Thymidylate Synthase / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymidylate Synthase
  • EGFR protein, human
  • ErbB Receptors
  • Fluorouracil