Potential Influence of ADAM9 Genetic Variants and Expression Levels on the EGFR Mutation Status and Disease Progression in Patients with Lung Adenocarcinoma
Abstract
:1. Introduction
2. Results
2.1. Demographic and Clinical Profiles of LUAD Patients with WT or Mutant EGFR
2.2. Distribution of ADAM9 Candidate SNPs (rs6474526, rs7006414, rs10105311, and rs78451751) Among LUAD Patients and Their Correlations with the EGFR Mutation Status
2.3. Associations Between ADAM9 Polymorphic Genotypes and Clinicopathological Features of LUAD Patients with WT or Mutant EGFR
2.4. Associations Between ADAM9 Polymorphic Genotypes and Clinicopathological Characteristics in Female LUAD Patients and Non-Smoking LUAD Patients
2.5. Potential Effects of ADAM9 Genetic Variants on ADAM9 Expression
2.6. Associations Between ADAM9 Expression Levels and Clinicopathological Characteristics as Well as Prognoses of LUAD Patients
2.7. Investigation of Potential Molecular Mechanisms Regulated by ADAM9 in LUAD Progression
3. Discussion
4. Materials and Methods
4.1. Study Populations and Ethics
4.2. Sequencing of EGFR from Tumor Tissues
4.3. Genotyping of ADAM9 SNPs from Whole-Blood Samples
4.4. Bioinformatics Analysis
4.5. Western Blot Analysis
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Variable | EGFR Wild-Type (N = 219) n (%) | EGFR Mutation (N = 316) n (%) | p-Value |
---|---|---|---|
Age (years) | |||
Mean ± SD | 64.63 ± 12.23 | 65.36 ± 12.51 | p = 0.523 |
Gender | |||
Male | 134 (61.2%) | 105 (33.2%) | p < 0.001 |
Female | 85 (38.8%) | 211 (66.8%) | |
Cigarette smoking status | |||
Never-smoker | 103 (47.0%) | 255 (80.7%) | p < 0.001 |
Ever-smoker | 116 (53.0%) | 61 (19.3%) | |
Stage | |||
I or II | 48 (21.9%) | 76 (24.1%) | p = 0.565 |
III or IV | 171 (78.1%) | 240 (75.9%) | |
Tumor T status | |||
T1 or T2 | 108 (49.3%) | 171 (54.1%) | p = 0.275 |
T3 or T4 | 111 (50.7%) | 145 (45.9%) | |
Lymph node status | |||
Negative | 59 (26.9%) | 89 (28.2%) | p = 0.756 |
Positive | 160 (73.1%) | 227 (71.8%) | |
Distant metastasis | |||
Negative | 97 (44.3%) | 126 (39.9%) | p = 0.308 |
Positive | 122 (55.7%) | 190 (60.1%) | |
Cell differentiation | |||
Well | 18 (8.2%) | 35 (11.1%) | p < 0.001 |
Moderately | 136 (62.1%) | 248 (78.5%) | |
Poorly | 65 (29.7%) | 33 (10.4%) |
Genotypes | EGFR Wild-Type (N = 219) | EGFR Mutation (N = 316) | AOR (95% CI) | p-Value |
---|---|---|---|---|
rs6474526 | ||||
TT | 192 (87.7%) | 296 (93.7%) | 1.000 | |
TG | 27 (12.3%) | 20 (6.3%) | 0.477 (0.260~0.875) | p = 0.017 * |
GG | 0 (0.0%) | 0 (0.0%) | --- | --- |
TG + GG | 27 (12.3%) | 20 (6.3%) | 0.477 (0.260~0.875) | p = 0.017 * |
rs7006414 | ||||
TT | 136 (62.1%) | 198 (62.7%) | 1.000 | |
TC | 67 (30.6%) | 102 (32.3%) | 1.156 (0.769~1.738) | p = 0.485 |
CC | 16 (7.3%) | 16 (5.0%) | 0.652 (0.302~1.412) | p = 0.278 |
TC + CC | 83 (37.9%) | 118 (37.3%) | 1.051 (0.717~1.540) | p = 0.799 |
rs10105311 | ||||
CC | 155 (70.8%) | 219 (69.3%) | 1.000 | |
CT | 56 (25.6%) | 83 (26.3%) | 1.073 (0.700~1.644) | p = 0.746 |
TT | 8 (3.6%) | 14 (4.4%) | 1.017 (0.397~2.607) | p = 0.972 |
CT + TT | 64 (29.2%) | 97 (30.7%) | 1.065 (0.711~1.595) | p = 0.759 |
rs78451751 | ||||
TT | 216 (98.6%) | 314 (99.4%) | 1.000 | |
TC | 3 (1.4%) | 2 (0.6%) | 0.372 (0.058~2.408) | p = 0.300 |
CC | 0 (0.0%) | 0 (0.0%) | --- | --- |
TC + CC | 3 (1.4%) | 2 (0.6%) | 0.372 (0.058~2.408) | p = 0.300 |
Variable | All (N = 535) | EGFR Wild-Type (N = 219) | EGFR Mutation (N = 316) | ||||||
---|---|---|---|---|---|---|---|---|---|
TT (N = 488) | TG + GG (N = 47) | p-Value | TT (N = 192) | TG + GG (N = 27) | p-Value | TT (N = 296) | TG + GG (N = 20) | p-Value | |
Stage | |||||||||
I or II | 116 (23.8%) | 8 (22.8%) | p = 0.295 | 42 (21.9%) | 6 (22.2%) | p = 0.967 | 74 (25.0%) | 2 (10.0%) | p = 0.129 |
III or IV | 372 (76.2%) | 39 (83.0%) | 150 (78.1%) | 21 (77.8%) | 222 (75.0%) | 18 (90.0%) | |||
Tumor T status | |||||||||
T1 or T2 | 262 (53.7%) | 17 (36.2%) | p = 0.022 a | 97 (50.5%) | 11 (40.7%) | p = 0.341 | 165 (55.7%) | 6 (30.0%) | p = 0.025 b |
T3 or T4 | 226 (46.3%) | 30 (63.8%) | 95 (49.5%) | 16 (59.3%) | 131 (44.3%) | 14 (70.0%) | |||
Lymph node status | |||||||||
Negative | 138 (28.3%) | 10 (21.3%) | p = 0.305 | 52 (27.1%) | 7 (25.9%) | p = 0.899 | 86 (29.1%) | 3 (15.0%) | p = 0.176 |
Positive | 350 (71.7%) | 37 (78.7%) | 140 (72.9%) | 20 (74.1%) | 210 (70.9%) | 17 (85.0%) | |||
Distant metastasis | |||||||||
Negative | 208 (42.6%) | 15 (31.9%) | p = 0.155 | 87 (45.3%) | 10 (37.0%) | p = 0.418 | 121 (40.9%) | 5 (25.0%) | p = 0.160 |
Positive | 280 (57.4%) | 32 (68.1%) | 105 (54.7%) | 17 (63.0%) | 175 (59.1%) | 15 (75.0%) | |||
Cell differentiation | |||||||||
Well/Moderately | 403 (82.6%) | 34 (72.3%) | p = 0.083 | 137 (71.4%) | 17 (63.0%) | p = 0.372 | 266 (89.9%) | 17 (85.0%) | p = 0.491 |
Poorly | 85 (17.4%) | 13 (27.7%) | 55 (28.6%) | 10 (37.0%) | 30 (10.1%) | 3 (15.0%) |
Variable | All (N = 535) | EGFR Wild-Type (N = 219) | EGFR Mutation (N = 316) | ||||||
---|---|---|---|---|---|---|---|---|---|
CC (N = 374) | CT + TT (N = 161) | p-Value | CC (N = 155) | CT + TT (N = 64) | p-Value | CC (N = 219) | CT + TT (N = 97) | p-Value | |
Stage | |||||||||
I or II | 82 (21.9%) | 42 (26.1%) | p = 0.295 | 28 (18.1%) | 20 (31.2%) | p = 0.032 a | 54 (24.7%) | 22 (22.7%) | p = 0.704 |
III or IV | 292 (78.1%) | 119 (73.9%) | 127 (81.9%) | 44 (68.8%) | 165 (75.3%) | 75 (77.3%) | |||
Tumor T status | |||||||||
T1 or T2 | 190 (50.8%) | 89 (55.3%) | p = 0.342 | 74 (47.7%) | 34 (53.1%) | p = 0.469 | 116 (53.0%) | 55 (56.7%) | p = 0.539 |
T3 or T4 | 184 (49.2%) | 72 (44.7%) | 81 (52.3%) | 30 (46.9%) | 103 (47.0%) | 42 (43.3%) | |||
Lymph node status | |||||||||
Negative | 102 (27.3%) | 46 (28.6%) | p = 0.758 | 36 (23.2%) | 23 (35.9%) | p = 0.054 | 66 (30.1%) | 23 (23.7%) | p = 0.241 |
Positive | 272 (72.7%) | 115 (71.4%) | 119 (76.8%) | 41 (64.1%) | 153 (69.9%) | 74 (76.3%) | |||
Distant metastasis | |||||||||
Negative | 149 (39.8%) | 74 (46.0%) | p = 0.188 | 63 (40.6%) | 34 (53.1%) | p = 0.091 | 86 (39.3%) | 40 (41.2%) | p = 0.742 |
Positive | 225 (60.2%) | 87 (54.0%) | 92 (59.4%) | 30 (46.9%) | 133 (60.7%) | 57 (58.8%) | |||
Cell differentiation | |||||||||
Well/Moderately | 306 (81.8%) | 131 (81.4%) | p = 0.901 | 113 (72.9%) | 41 (64.1%) | p = 0.193 | 193 (88.1%) | 90 (92.8%) | p = 0.212 |
Poorly | 68 (18.2%) | 30 (18.6%) | 42 (27.1%) | 23 (35.9%) | 26 (11.9%) | 7 (7.2%) |
Variable | Female (N = 296) | Non-Smoker (N = 358) | ||||||
---|---|---|---|---|---|---|---|---|
TT (N = 278) | TG + GG (N = 18) | OR (95% CI) | p-Value | TT (N = 336) | TG + GG (N = 22) | OR (95% CI) | p-Value | |
Stage | ||||||||
I or II | 73 (26.3%) | 2 (11.1%) | 1.000 | p = 0.152 | 87 (25.9%) | 2 (9.1%) | 1.000 | p = 0.077 |
III or IV | 205 (73.7%) | 16 (88.9%) | 2.849 (0.639~12.692) | 249 (74.1%) | 20 (90.9%) | 3.494 (0.800~15.256) | ||
Tumor T status | ||||||||
T1 or T2 | 156 (56.1%) | 4 (22.2%) | 1.000 | p = 0.005 | 185 (55.1%) | 4 (18.2%) | 1.000 | p = 0.001 |
T3 or T4 | 122 (43.9%) | 14 (77.8%) | 4.475 (1.437~13.940) | 151 (44.9%) | 18 (81.8%) | 5.513 (1.827~16.638) | ||
Lymph node status | ||||||||
Negative | 89 (32.0%) | 3 (16.7%) | 1.000 | p = 0.173 | 101 (30.1%) | 4 (18.2%) | 1.000 | p = 0.236 |
Positive | 189 (68.0%) | 15 (83.3%) | 2.354 (0.665~8.342) | 235 (69.9%) | 18 (81.8%) | 1.934 (0.639~5.858) | ||
Distant metastasis | ||||||||
Negative | 118 (42.4%) | 3 (16.7%) | 1.000 | p = 0.031 | 140 (41.7%) | 3 (13.6%) | 1.000 | p = 0.009 |
Positive | 160 (57.6%) | 15 (83.3%) | 3.688 (1.044~13.029) | 196 (58.3%) | 19 (86.4%) | 4.524 (1.313~15.583) | ||
Cell differentiation | ||||||||
Well/ Moderately | 243 (87.4%) | 14 (77.8%) | 1.000 | p = 0.242 | 288 (85.7%) | 16 (72.7%) | 1.000 | p = 0.099 |
Poorly | 35 (12.6%) | 4 (22.2%) | 1.984 (0.618~6.368) | 48 (14.3%) | 6 (27.3%) | 2.250 (0.839~6.036) |
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Chang, J.-H.; Lai, T.-C.; Ho, K.-H.; Tsao, T.C.-Y.; Chang, L.-C.; Yang, S.-F.; Chien, M.-H. Potential Influence of ADAM9 Genetic Variants and Expression Levels on the EGFR Mutation Status and Disease Progression in Patients with Lung Adenocarcinoma. Int. J. Mol. Sci. 2025, 26, 4606. https://doi.org/10.3390/ijms26104606
Chang J-H, Lai T-C, Ho K-H, Tsao TC-Y, Chang L-C, Yang S-F, Chien M-H. Potential Influence of ADAM9 Genetic Variants and Expression Levels on the EGFR Mutation Status and Disease Progression in Patients with Lung Adenocarcinoma. International Journal of Molecular Sciences. 2025; 26(10):4606. https://doi.org/10.3390/ijms26104606
Chicago/Turabian StyleChang, Jer-Hwa, Tsung-Ching Lai, Kuo-Hao Ho, Thomas Chang-Yao Tsao, Lun-Ching Chang, Shun-Fa Yang, and Ming-Hsien Chien. 2025. "Potential Influence of ADAM9 Genetic Variants and Expression Levels on the EGFR Mutation Status and Disease Progression in Patients with Lung Adenocarcinoma" International Journal of Molecular Sciences 26, no. 10: 4606. https://doi.org/10.3390/ijms26104606
APA StyleChang, J.-H., Lai, T.-C., Ho, K.-H., Tsao, T. C.-Y., Chang, L.-C., Yang, S.-F., & Chien, M.-H. (2025). Potential Influence of ADAM9 Genetic Variants and Expression Levels on the EGFR Mutation Status and Disease Progression in Patients with Lung Adenocarcinoma. International Journal of Molecular Sciences, 26(10), 4606. https://doi.org/10.3390/ijms26104606