Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients
Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloprot...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/21/8023 |
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| author | Jer-Hwa Chang Tsung-Ching Lai Po-Jen Yang Pei-Chun Shih Yi-Chieh Yang Kai-Ling Lee Tu-Chen Liu Thomas Chang-Yao Tsao Shun-Fa Yang Ming-Hsien Chien |
| author_facet | Jer-Hwa Chang Tsung-Ching Lai Po-Jen Yang Pei-Chun Shih Yi-Chieh Yang Kai-Ling Lee Tu-Chen Liu Thomas Chang-Yao Tsao Shun-Fa Yang Ming-Hsien Chien |
| author_sort | Jer-Hwa Chang |
| collection | DOAJ |
| description | Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purpose of this study was to investigate potential associations among TIMP-3 genetic polymorphisms, EGFR statuses, and cancer clinicopathologic development in patients with LADC. In this study, 277 LADC patients with different EGFR statuses were recruited to dissect the allelic discrimination of TIMP-3 -1296 T>C (rs9619311), TIMP3 249T>C (rs9862), and TIMP3 261C>T (rs11547635) polymorphisms using a TaqMan allelic discrimination assay. Our data showed that compared to those LADC patients with wild-type CC homozygotes of TIMP-3 rs9862, patients harboring TT homozygotes of rs9862 were at a higher risk of developing mutant EGFR (adjusted odds ratio (AOR) = 2.530; 95% confidence interval (CI): 1.230–5.205; <i>p</i> = 0.012), particularly the EGFR L858R point mutation (AOR = 2.975; 95% CI: 1.182–7.488; <i>p</i> = 0.021). Moreover, we observed that TIMP-3 TT homozygotes of rs9862 were correlated with the incidence of EGFR mutations in patients with a smoking habit (<i>p</i> = 0.045). Within male patients harboring a mutant EGFR, TIMP-3 rs9862 T (CT+TT) allele carriers were at higher risk of developing an advanced stage (<i>p</i> = 0.025) and lymph node metastasis (<i>p</i> = 0.043). Further analyses of clinical datasets revealed correlations of TIMP-3 expression with a favorable prognosis in patients with LADC. In conclusion, the data suggest that TIMP-3 rs9862 polymorphisms may contribute to identify subgroups of lung cancer patients at high risk for tumor progression, among carriers of LADC-bearing mutant EGFR. |
| first_indexed | 2024-03-10T15:16:36Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:16:36Z |
| publishDate | 2020-10-01 |
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| spelling | doaj.art-32336bd5ee9c4ef9bd0d841c056fc2192023-11-20T18:52:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012121802310.3390/ijms21218023Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma PatientsJer-Hwa Chang0Tsung-Ching Lai1Po-Jen Yang2Pei-Chun Shih3Yi-Chieh Yang4Kai-Ling Lee5Tu-Chen Liu6Thomas Chang-Yao Tsao7Shun-Fa Yang8Ming-Hsien Chien9School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDivision of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, TaiwanSchool of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanDepartment of Laboratory Medicine, National Taiwan University Hospital, Taipei 100225, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Chest Medicine, Cheng-Ching General Hospital, Taichung 407, TaiwanSchool of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanPulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, TaiwanLung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purpose of this study was to investigate potential associations among TIMP-3 genetic polymorphisms, EGFR statuses, and cancer clinicopathologic development in patients with LADC. In this study, 277 LADC patients with different EGFR statuses were recruited to dissect the allelic discrimination of TIMP-3 -1296 T>C (rs9619311), TIMP3 249T>C (rs9862), and TIMP3 261C>T (rs11547635) polymorphisms using a TaqMan allelic discrimination assay. Our data showed that compared to those LADC patients with wild-type CC homozygotes of TIMP-3 rs9862, patients harboring TT homozygotes of rs9862 were at a higher risk of developing mutant EGFR (adjusted odds ratio (AOR) = 2.530; 95% confidence interval (CI): 1.230–5.205; <i>p</i> = 0.012), particularly the EGFR L858R point mutation (AOR = 2.975; 95% CI: 1.182–7.488; <i>p</i> = 0.021). Moreover, we observed that TIMP-3 TT homozygotes of rs9862 were correlated with the incidence of EGFR mutations in patients with a smoking habit (<i>p</i> = 0.045). Within male patients harboring a mutant EGFR, TIMP-3 rs9862 T (CT+TT) allele carriers were at higher risk of developing an advanced stage (<i>p</i> = 0.025) and lymph node metastasis (<i>p</i> = 0.043). Further analyses of clinical datasets revealed correlations of TIMP-3 expression with a favorable prognosis in patients with LADC. In conclusion, the data suggest that TIMP-3 rs9862 polymorphisms may contribute to identify subgroups of lung cancer patients at high risk for tumor progression, among carriers of LADC-bearing mutant EGFR.https://www.mdpi.com/1422-0067/21/21/8023tissue inhibitor of metalloproteinases-3polymorphismepidermal growth factor receptormutationlung adenocarcinoma |
| spellingShingle | Jer-Hwa Chang Tsung-Ching Lai Po-Jen Yang Pei-Chun Shih Yi-Chieh Yang Kai-Ling Lee Tu-Chen Liu Thomas Chang-Yao Tsao Shun-Fa Yang Ming-Hsien Chien Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients International Journal of Molecular Sciences tissue inhibitor of metalloproteinases-3 polymorphism epidermal growth factor receptor mutation lung adenocarcinoma |
| title | Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients |
| title_full | Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients |
| title_fullStr | Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients |
| title_full_unstemmed | Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients |
| title_short | Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients |
| title_sort | associations of i timp 3 i genetic polymorphisms with i egfr i statuses and cancer clinicopathologic development in lung adenocarcinoma patients |
| topic | tissue inhibitor of metalloproteinases-3 polymorphism epidermal growth factor receptor mutation lung adenocarcinoma |
| url | https://www.mdpi.com/1422-0067/21/21/8023 |
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