Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients
Abstract
:1. Introduction
2. Results
2.1. General Characteristics of LADC Patients Harboring the Wild-Type (WT) or Mutant EGFR
2.2. Associations between TIMP-3 Candidate SNPs (rs9619311, rs9862, and rs11547635) and EGFR Mutations in LADC Patients with or without Cigarette Consumption
2.3. Correlations between Polymorphic Genotypes of TIMP-3 and Clinicopathological Characteristics of LADC Patients of Different Genders with the WT or Mutant EGFR
3. Discussion
4. Materials and Methods
4.1. Patient Specimens
4.2. DNA Extraction and EGFR Gene Sequencing from Tumor Tissues
4.3. Genomic TIMP3 SNPs Detected from Blood
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AORs | Adjusted odds ratios |
CIs | Confidence intervals |
EGFR | Epidermal growth factor receptor |
GTEx | Genotype-Tissue Expression |
LADC | Lung adenocarcinoma |
MMP | Matrix metalloproteinase |
NSCLC | Non-small-cell lung cancer |
SCC | Squamous cell carcinoma |
SNPs | Single-nucleotide polymorphisms |
TCGA | The Cancer Genome Atlas |
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Subject Characteristic | Wild-Type (N = 109) | Mutation Type (N = 168) | p Value |
---|---|---|---|
Age, | |||
mean ± SD (years) | 65.45 ± 13.34 | 65.69 ± 13.58 | 0.885 |
Gender, n (%) | |||
Male | 65 (59.6%) | 60 (35.7%) | <0.001 |
Female | 44 (40.4%) | 108 (64.3%) | |
Cigarette smoking, n (%) | |||
Non-smoker | 49 (45.0%) | 130 (77.4%) | <0.001 |
Ever-smoker | 60 (55.0%) | 38 (22.6%) | |
Stage, n (%) | |||
I+II | 25 (22.9%) | 47 (28.0%) | 0.350 |
III+IV | 84 (77.1%) | 121 (72.0%) | |
Tumor T status, n (%) | |||
T1+T2 | 59 (54.1%) | 107 (63.7%) | 0.113 |
T3+T4 | 50 (45.9%) | 61 (36.3%) | |
Lymph node status, n (%) | |||
Negative | 28 (25.7%) | 53 (31.5%) | 0.295 |
Positive | 81 (74.3%) | 115 (68.5%) | |
Distant metastasis, n (%) | |||
Negative | 53 (48.6%) | 80 (47.6%) | 0.870 |
Positive | 56 (51.4%) | 88 (52.4%) | |
Cell differentiation, n (%) | |||
Well/Moderately | 87 (79.8%) | 158 (94.0%) | <0.001 |
Poorly | 22 (20.2%) | 10 (6.0%) |
Genotype SNP | Wild-Type (N = 109) | Mutation Type (N = 168) | AOR (95% CI) | p-Value |
---|---|---|---|---|
rs9619311 | ||||
TT | 89 (81.7%) | 133 (79.2%) | 1.00 | |
TC | 19 (17.4%) | 33 (19.6%) | 1.228 (0.621–2.428) | 0.555 |
CC | 1 (0.9%) | 2 (1.2%) | 1.229 (0.103–14.708) | 0.871 |
TC+CC | 20 (18.3%) | 35 (20.8%) | 1.228 (0.631–2.390) | 0.545 |
rs9862 | ||||
CC | 43 (39.4%) | 49 (29.2%) | 1.00 | |
CT | 47 (43.1%) | 69 (41.1%) | 1.423 (0.778–2.602) | 0.252 |
TT | 19 (17.4%) | 50 (29.7%) | 2.530 (1.230–5.205) | 0.012 * |
CT+TT | 66 (60.6%) | 119 (70.8%) | 1.748 (1.002–3.048) | 0.049 * |
rs11547635 | ||||
CC | 52 (47.7%) | 85 (50.6%) | 1.00 | |
CT | 44 (40.4%) | 68 (40.5%) | 0.891 (0.514–1.544) | 0.680 |
TT | 13 (11.9%) | 15 (8.9%) | 0.611 (0.253–1.474) | 0.273 |
CT+TT | 57 (52.3%) | 83 (49.4%) | 0.826 (0.492–1.387) | 0.469 |
Genotype SNP | Non-Smoking (N = 179) | Smoking (N = 98) | ||||
---|---|---|---|---|---|---|
Wild-Type (N = 49) | Mutation Type (N = 130) | p-Value | Wild-Type (N = 60) | Mutation Type (N = 38) | p-Value | |
rs9619311 | ||||||
TT | 39 (79.6%) | 106 (81.5%) | 50 (83.3%) | 27 (71.1%) | ||
TC | 9 (18.4%) | 23 (17.7%) | 0.675 | 10 (16.7%) | 10 (26.3%) | 0.268 |
CC | 1 (2.0%) | 1 (0.8%) | 0.423 | 0 (0.0%) | 1 (2.6%) | – |
TC+CC | 10 (20.4%) | 24 (18.5%) | 0.556 | 10 (16.7%) | 11 (28.9%) | 0.190 |
rs9862 | ||||||
CC | 18 (36.7%) | 42 (32.3%) | 25 (41.7%) | 7 (18.4%) | ||
CT | 22 (44.9%) | 50 (38.5%) | 0.853 | 25 (41.7%) | 19 (50.0%) | 0.169 |
TT | 9 (18.4%) | 38 (29.2%) | 0.116 | 10 (16.6%) | 12 (31.6%) | 0.045 *,a |
CT+TT | 31 (63.3%) | 88 (67.7%) | 0.386 | 35 (58.3%) | 31 (81.6%) | 0.070 |
rs11547635 | ||||||
CC | 25 (51.0%) | 62 (47.7%) | 27 (45.0%) | 23 (60.5%) | ||
CT | 18 (36.7%) | 55 (42.3%) | 0.736 | 26 (43.3%) | 13 (34.2%) | 0.235 |
TT | 6 (12.3%) | 13 (10.0%) | 0.661 | 7 (11.7%) | 2 (5.3%) | 0.317 |
CT+TT | 24 (49.0%) | 68 (52.3%) | 0.903 | 33 (55.0%) | 15 (39.5%) | 0.168 |
SNP Genotypes | Wild-Type (N = 109) | L858R | Exon 19 In-Frame Deletion | ||
---|---|---|---|---|---|
(N = 78) | AOR (95% CI) | (N = 81) | AOR (95% CI) | ||
rs9619311 | |||||
TT | 89 (81.7%) | 64 (82.1%) | 1.00 | 64 (79.0%) | 1.00 |
TC | 19 (17.4%) | 13 (16.7%) | 0.701 (0.277–1.772) | 16 (19.8%) | 1.147 (0.514–2.557) |
CC | 1 (0.9%) | 1 (1.2%) | 0.560 (0.033–9.449) | 1 (1.2%) | 1.340 (0.081–22.202) |
TC+CC | 20 (18.3%) | 14 (17.9%) | 0.689 (0.280–1.695) | 17 (21.0%) | 1.157 (0.529–2.534) |
rs9862 | |||||
CC | 43 (39.4%) | 23 (29.5%) | 1.00 | 23 (28.4%) | 1.00 |
CT | 47 (43.1%) | 30 (38.5%) | 1.343 (0.614–2.938) | 37 (45.7%) | 1.560 (0.760–3.204) |
TT | 19 (17.4%) | 25 (32.0%) | 2.975 (1.182–7.488) a | 21 (25.9%) | 2.295 (0.973–5.412) |
CT+TT | 66 (60.6%) | 55 (70.5%) | 1.787 (0.873–3.661) | 58 (71.6%) | 1.772 (0.908–3.458) |
rs11547635 | |||||
CC | 52 (47.7%) | 40 (51.3%) | 1.00 | 39 (48.1%) | 1.00 |
CT | 44 (40.4%) | 32 (41.0%) | 1.005 (0.493–2.046) | 33 (40.7%) | 0.932 (0.486–1.787) |
TT | 13 (11.9%) | 6 (7.7%) | 0.536 (0.166–1.731) | 9 (11.2%) | 0.885 (0.325–2.410) |
CT+TT | 57 (52.3%) | 38 (48.7%) | 0.883 (0.453–1.722) | 42 (51.9%) | 0.922 (0.499–1.702) |
Variable | All (N = 277) | Males (N = 125) | Females (N = 152) | ||||||
---|---|---|---|---|---|---|---|---|---|
CC (N = 92) | CT+TT (N = 185) | p-Value | CC (N = 39) | CT+TT (N = 86) | p-Value | CC (N = 53) | CT+TT (N = 99) | p-Value | |
Stage | |||||||||
I+II | 26 (28.3%) | 46 (24.9%) | 0.544 | 13 (33.3%) | 14 (16.3%) | 0.032 *,a | 13 (24.5%) | 32 (32.3%) | 0.316 |
III+IV | 66 (71.7%) | 107 (75.1%) | 26 (66.7%) | 72 (83.7%) | 40 (75.5%) | 67 (67.7%) | |||
Tumor T status | |||||||||
T1+T2 | 58 (63.0%) | 108 (58.4%) | 0.456 | 24 (61.5%) | 47 (54.7%) | 0.471 | 34 (64.2%) | 61 (61.6%) | 0.758 |
T3+T4 | 34 (37.0%) | 77 (41.6%) | 15 (38.5%) | 39 (45.3%) | 19 (35.8%) | 38 (38.4%) | |||
Lymph node status | |||||||||
Negative | 29 (31.5%) | 52 (28.1%) | 0.556 | 10 (25.6%) | 19 (22.1%) | 0.663 | 19 (35.8%) | 33 (33.3%) | 0.755 |
Positive | 63 (68.5%) | 133 (71.9%) | 29 (74.4%) | 67 (77.9%) | 34 (64.2%) | 66 (66.7%) | |||
Distant metastasis | |||||||||
Negative | 42 (45.7%) | 91 (49.2%) | 0.579 | 19 (48.7%) | 38 (44.2%) | 0.637 | 23 (43.4%) | 53 (53.5%) | 0.233 |
Positive | 50 (54.3%) | 94 (50.8%) | 20 (51.3%) | 48 (55.8%) | 30 (56.6%) | 46 (46.5%) | |||
Cell differentiation | |||||||||
Well/Moderately | 84 (91.3%) | 161 (87.0%) | 0.294 | 33 (84.6%) | 69 (80.2%) | 0.558 | 51 (96.2%) | 92 (92.9%) | 0.412 |
Poorly | 8 (8.7%) | 24 (13.0%) | 6 (15.4%) | 17 (19.8%) | 2 (3.8%) | 7 (7.1%) |
Variable | Wild-type (N = 65) | Mutation type (N = 60) | ||||
---|---|---|---|---|---|---|
CC (N = 24) | CT+TT (N = 41) | p-Value | CC (N = 15) | CT+TT (N = 45) | p-Value | |
Stage | ||||||
I+II | 6 (25.0%) | 6 (14.6%) | 0.299 | 7 (46.7%) | 8 (17.8%) | 0.025 *,a |
III+IV | 18 (75.0%) | 35 (85.4%) | 8 (53.3%) | 37 (82.2%) | ||
Tumor T status | ||||||
T1+T2 | 15 (62.5%) | 21 (51.2%) | 0.377 | 9 (60.0%) | 15 (57.8%) | 0.880 |
T3+T4 | 9 (37.5%) | 20 (48.8%) | 6 (40.0%) | 19 (42.2%) | ||
Lymph node status | ||||||
Negative | 3 (12.5%) | 10 (24.4%) | 0.247 | 7 (46.7%) | 9 (20.0%) | 0.043 *,b |
Positive | 21 (87.5%) | 31 (75.6%) | 8 (53.3%) | 36 (80.0%) | ||
Distant metastasis | ||||||
Negative | 11 (45.8%) | 20 (48.8%) | 0.818 | 8 (53.3%) | 18 (40.0%) | 0.367 |
Positive | 13 (54.2%) | 21 (51.2%) | 7 (46.7%) | 27 (60.0%) | ||
Cell differentiation | ||||||
Well/Moderately | 19 (79.2%) | 30 (73.2%) | 0.588 | 14 (93.3%) | 39 (86.7%) | 0.486 |
Poorly | 5 (20.8%) | 11 (26.8%) | 1 (6.7%) | 6 (13.3%) |
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Chang, J.-H.; Lai, T.-C.; Yang, P.-J.; Shih, P.-C.; Yang, Y.-C.; Lee, K.-L.; Liu, T.-C.; Tsao, T.C.-Y.; Yang, S.-F.; Chien, M.-H. Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients. Int. J. Mol. Sci. 2020, 21, 8023. https://doi.org/10.3390/ijms21218023
Chang J-H, Lai T-C, Yang P-J, Shih P-C, Yang Y-C, Lee K-L, Liu T-C, Tsao TC-Y, Yang S-F, Chien M-H. Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients. International Journal of Molecular Sciences. 2020; 21(21):8023. https://doi.org/10.3390/ijms21218023
Chicago/Turabian StyleChang, Jer-Hwa, 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, and Ming-Hsien Chien. 2020. "Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients" International Journal of Molecular Sciences 21, no. 21: 8023. https://doi.org/10.3390/ijms21218023