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.

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.

• 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
• Journal: Clinical lung cancer (Clin Lung Cancer) Vol. 15 Issue 2 Pg. 136-144.e4 (Mar 2014) ISSN: 1938-0690 [Electronic] United States
• PMID: 24405586 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Aged
• Antimetabolites, Antineoplastic (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Carcinoma, Squamous Cell (drug therapy, genetics, metabolism, pathology)
• Dihydrouracil Dehydrogenase (NADP) (genetics, metabolism)
• ErbB Receptors (genetics, metabolism)
• Female
• Fluorouracil (therapeutic use)
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Mutation (genetics)
• Neoplasm Staging
• Polymerase Chain Reaction
• Prognosis
• Thymidylate Synthase (genetics, metabolism)