<i>EGFR</i> exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

Yang, Shan; Yang, Tsung Ying; Li, Yao Jen; Chen, Kun Chieh; Liao, Kuo Meng; Hsu, Kuo-Hsuan; Tsai, Chia-Lung; Chen, Chih Yi; Hsu, Chiao Po; Hsia, Jiun-Yi; Chuang, Chun‐Yi; Tsai, Ying Huang; Chen, Kuan‐Yu; Huang, Ming Shyan; Su, Wu Chou; Chen, Yuh Min; Hsiung, Chao A.; Shen, Chen; Chang, Gee Chen; Yang, Pan Chyr; Chen, Chien Jen

doi:10.1002/ijc.27630

Cited by 12 publications

(7 citation statements)

References 46 publications

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“…Our previous report indicated that the association between the increase in 8‐OH‐dG levels due to human papillomavirus (HPV) 16/18 infection and the occurrence of EGFR mutations in patients with NSCLC might be due to a reduction in DNA repair capabilities 19 . Other groups have reported an association between lower ERCC1 expression, the SNP rs744154c in ERCC4 , and EGFR exon 19 deletion mutations, thereby revealing the possibility that EGFR exon 19 deletion mutations could be associated with decreasing DNA repair capabilities 20,21 . In the present study, we observed that EGFR deletion mutations in exon 19 were more common in patients with hOGG1 ‐Cys variants with less ability to remove 8‐OH‐dG than with hOGG1 Ser/Ser genotype.…”

Section: Discussionsupporting

confidence: 58%

Association of hOGG1‐Cys variants with occurrence of p53 and EGFR deletion mutations in non‐small cell lung cancer

et al. 2020

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Background The human 8‐oxoguanine DNA glycosylase 1 (hOGG1) gene encodes a DNA glycosylase that removes 8‐hydroxy‐2‐deoxyguanine (8‐OH‐dG) DNA damage to protect against gene mutations. The association of hOGG1 Ser326Cys polymorphism with lung cancer risk has predicted that hOGG1‐Cys variants are less effective at removing 8‐OH‐dG damage from DNA; therefore, these variants might show an increased occurrence of tumor suppressor gene and oncogene mutations. However, no evidence has yet supported this hypothesis. Methods Direct sequencing was performed to examine the mutations of p53 and EGFR genes in lung tumors from patients with non‐small cell lung cancer (NSCLC). Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to examine hOGG1 Ser326Cys polymorphism in this study population. Results A total of 99 p53‐mutated and 99 EGFR‐mutated patients with NSCLC were selected to explore the possible associations of these mutations with hOGG1 Ser326Cys polymorphism. The p53‐mutated and EGFR‐mutated patients were divided into nondeletion and deletion subgroups. P53 deletion mutations were more commonly observed in male than in female patients (P = 0.030). However, EGFR exon 19 deletion mutations were more prevalent in female and adenocarcinoma patients than in male and squamous cell carcinoma patients (P = 0.028 for genders, P = 0.017 for tumor histology). Interestingly, p53 and EGFR exon 19 deletion mutations were more frequent in patients with hOGG1 Ser/Cys + Cys/Cys hOGG1‐Cys variants than with the hOGG1 Ser/Ser genotype (P = 0.010 for p53, P = 0.032 for EGFR). Conclusions We suggest that the association of hOGG1 Ser326Cys polymorphism with lung cancer risk could be partially explained by increases in p53 and EGFR deletion mutations. Key points Significant findings of the study NSCLC patients with hOGG1‐Cys variants may have a higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. What this study adds NSCLC patients with hOGG1‐Cys variants might be helpful to predict patients having higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib or erlotinib could be a higher risk to occur EGFR T790M mutation.

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Section: Discussionsupporting

confidence: 58%

Association of hOGG1‐Cys variants with occurrence of p53 and EGFR deletion mutations in non‐small cell lung cancer

et al. 2020

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“…Among the DNA repair system, Exo1 is the only exonuclease involved in the human MMR system, one of the major roles is the MMR system which is responsible for correcting mismatches between bases and small insertion or deletion loops [32], [33]. Although many SNPs in NQO1, CYP1A1, ERCC4, EXO1, MSH2, XRCC1 and hOGG1 have been identified, only some of them have been extensively investigated in epidemiological studies [34], SNPs for which potential functional evidence in the development, progression and metastasis of cancer remains unknown, especially for Exo1 gene.…”

Section: Discussionmentioning

confidence: 99%

The Significance of Exo1 K589E Polymorphism on Cancer Susceptibility: Evidence Based on a Meta-Analysis

et al. 2014

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The exonuclease1 (Exo1) gene is a key component of mismatch repair (MMR) by resecting the damaged strand, which is the only exonuclease involved in the human MMR system. The gene product is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. However, whether Exo1 is required to activate MMR-dependent DNA damage response (DDR) remains unknown, the conclusions of the Exo1 polymorphisms on cancer susceptibility studies were not consistent. We carried out a meta-analysis of 7 case-control studies to clarify the association between the Exo1 K589E polymorphism and cancer risk. Overall,a significant association of the Exo1 K589E polymorphism with cancer risk in all genetic models (Lys vs Glu: OR = 1.51, 95%CI:1.39–1.99, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.43, 95%CI:1.28–1.60, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.45, 95%CI:1.90–3.17, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.53, 95%CI:1.38–1.71, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.27, 95%CI:1.79–2.89, P<0.01). In the stratified analysis by ethnicity, significantly increased risk was observed in Asian population (Lys vs Glu: OR = 1.53, 95%CI:1.39–1.69, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.50, 95%CI:1.34–1.69, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.48, 95%CI:1.84–3.34, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.58, 95%CI:1.41–1.78, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.18, 95%CI:1.62–2.93, P<0.01). Subgroup analysis based on smoking suggested Exo1 K589E polymorphism conferred significant risk among smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 2.16, 95%CI:1.77–2.63, P<0.01), but not in non-smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 0.89, 95%CI:0.64–1.24, P = 0.50). In conclusion, Exo1 K589E Lys allele may be used as a novel biomarker for cancer susceptibility, particularly in smokers.

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“…It not only catalyzes the two electron reduction of quinones into the hydroquinones in a reaction that prevents the production of harmful semiquinones and ROS [ 16 , 38 ] but also stabilizes the tumor suppressor TP53 [ 11 ]. The C609T polymorphisms in NQO1 may be a predictive factor for survival after resection of NSCLC tumors [ 39 ] and the rs1800566C/T SNP within NQO1 is linked to the deletion of EGFR exon 19 in NSCLC patients [ 40 ]. Eighty-four percent of the NQO1(-/-), but none of the control mice, exposed to gamma irradiation develop NSCLC [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Increased NQO1 but Not c-MET and Survivin Expression in Non-Small Cell Lung Carcinoma with KRAS Mutations

Yılmaz

Mohamed

Patterson

et al. 2014

IJERPH

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Cigarette smoking is one of the most significant public health issues and the most common environmental cause of preventable cancer deaths worldwide. EGFR (Epidermal Growth Factor Receptor)-targeted therapy has been used in the treatment of LC (lung cancer), mainly caused by the carcinogens in cigarette smoke, with variable success. Presence of mutations in the KRAS (Kirsten rat sarcoma viral oncogene homolog) driver oncogene may confer worse prognosis and resistance to treatment for reasons not fully understood. NQO1 (NAD(P)H:quinone oxidoreductase), also known as DT-diaphorase, is a major regulator of oxidative stress and activator of mitomycins, compounds that have been targeted in over 600 pre-clinical trials for treatment of LC. We sequenced KRAS and investigated expression of NQO1 and five clinically relevant proteins (DNMT1, DNMT3a, ERK1/2, c-MET, and survivin) in 108 patients with non-small cell lung carcinoma (NSCLC). NQO1, ERK1/2, DNMT1, and DNMT3a but not c-MET and survivin expression was significantly more frequent in patients with KRAS mutations than those without, suggesting the following: (1) oxidative stress may play an important role in the pathogenesis, worse prognosis, and resistance to treatment reported in NSCLC patients with KRAS mutations, (2) selecting patients based on their KRAS mutational status for future clinical trials may increase success rate, and (3) since oxidation of nucleotides also specifically induces transversion mutations, the high rate of KRAS transversions in lung cancer patients may partly be due to the increased oxidative stress in addition to the known carcinogens in cigarette smoke.

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EGFR exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

Cited by 12 publications

References 46 publications

Association of hOGG1‐Cys variants with occurrence of p53 and EGFR deletion mutations in non‐small cell lung cancer

Association of hOGG1‐Cys variants with occurrence of p53 and EGFR deletion mutations in non‐small cell lung cancer

The Significance of Exo1 K589E Polymorphism on Cancer Susceptibility: Evidence Based on a Meta-Analysis

Increased NQO1 but Not c-MET and Survivin Expression in Non-Small Cell Lung Carcinoma with KRAS Mutations

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