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The close correlation between 8-hydroxy-2'-deoxyguanosine and epidermal growth factor receptor activating mutation in
Akihiko Kawahara1, Koichi Azuma, Satoshi Hattori
1Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan.
Abstract:
Patients with non-small cell lung cancer harboring mutations in the epidermal growth factor receptor gene, including delE746-A750 and L858R, are highly sensitive to therapy with epidermal growth factor receptor-targeting drugs, such as gefitinib and erlotinib, in comparison with those harboring wild-type epidermal growth factor receptor. It remains unclear how such epidermal growth factor receptor mutations are induced. In this study, we examined whether 8-hydroxy-2'-deoxyguanosine, a representative oxygen nucleotide of DNA, could play a role in activating mutations of the epidermal growth factor receptor gene and also whether Y-box binding protein-1 and 8-oxoguanine DNA glycosylase that are involved in repair of oxidative stimuli-induced DNA damages could play any role in epidermal growth factor receptor activating mutations. Immunohistochemistry was used to evaluate the expression of 8-hydroxy-2'-deoxyguanosine, Y-box binding protein-1, and 8-oxoguanine DNA glycosylase in patients with non-small cell lung cancer (N = 170). We analyzed mutations of delE746-A750 and L858R in the epidermal growth factor receptor gene using peptide nucleic acid-locked nucleic acid polymerase chain reaction clamping. In non-small cell lung cancer patients, nuclear 8-hydroxy-2'-deoxyguanosine expression was strongly associated with these epidermal growth factor receptor mutations. Furthermore, nuclear expression of Y-box binding protein-1 was inversely associated with epidermal growth factor receptor mutations; but nuclear expression of 8-oxoguanine DNA glycosylase was not. Among 51 patients who were treated with gefitinib, progression-free survival was substantially better when 8-hydroxy-2'-deoxyguanosine expression was positive, when epidermal growth factor receptor mutations were present, and when nuclear Y-box binding protein-1 expression was negative. Thus, activating mutations of the epidermal growth factor receptor gene in non-small cell lung cancer were closely associated with a decrease in the damage repair process for 8-hydroxy-2'-deoxyguanosine in oxidized DNA.
Insights
Oxidative DNA damage, specifically 8-hydroxy-2'-deoxyguanosine, is linked to epidermal growth factor receptor mutations in non-small cell lung cancer. Reduced DNA repair capacity may drive these activating mutations, impacting treatment response.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) patients with specific epidermal growth factor receptor (EGFR) mutations (delE746-A750, L858R) show high sensitivity to EGFR-targeting drugs.
- The mechanisms inducing these activating EGFR mutations remain unclear.
- Oxidative stress and DNA damage repair pathways are potential contributors to oncogene mutations.
Purpose of the Study:
- To investigate the role of 8-hydroxy-2 -deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in the induction of EGFR activating mutations in NSCLC.
- To examine the involvement of Y-box binding protein-1 (YB-1) and 8-oxoguanine DNA glycosylase (OGG1) in the repair of oxidative DNA damage and their potential role in EGFR mutations.
- To correlate the expression of these molecules with EGFR mutation status and gefitinib treatment outcomes in NSCLC patients.
Main Methods:
- Immunohistochemistry was employed to assess the expression levels of 8-OHdG, YB-1, and OGG1 in tumor tissues from 170 NSCLC patients.
- EGFR mutations (delE746-A750 and L858R) were analyzed using peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamping.
- Progression-free survival (PFS) was evaluated in a subset of 51 patients treated with gefitinib.
Main Results:
- Nuclear 8-OHdG expression was significantly associated with the presence of EGFR activating mutations (delE746-A750 and L858R) in NSCLC.
- Nuclear YB-1 expression showed an inverse correlation with EGFR mutations, while OGG1 expression did not show a significant association.
- In gefitinib-treated patients, positive 8-OHdG expression, presence of EGFR mutations, and negative nuclear YB-1 expression were associated with substantially better progression-free survival.
Conclusions:
- Activating EGFR mutations in NSCLC are closely linked to a diminished DNA damage repair process for 8-OHdG in oxidized DNA.
- Reduced capacity to repair oxidative DNA damage may be a key factor in the development of EGFR-activating mutations.
- These findings suggest that markers of oxidative stress and DNA repair could inform patient stratification and treatment strategies for NSCLC.
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