The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Patient Specimens
4.2. Genomic DNA Extraction and Insulin-Like Growth Factor 1 Receptor (IGF1R) Genotyping
4.3. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
IGF1 | insulin-like growth factor 1 |
IGF1R | insulin-like growth factor 1 receptor |
EGFR | epidermal growth factor receptor |
NSCLC | non-small-cell lung carcinoma |
References
- Travis, W.D. The 2015 who classification of lung tumors. Der Pathol. 2014, 35, 188. [Google Scholar] [CrossRef] [PubMed]
- Sharma, S.V.; Bell, D.W.; Settleman, J.; Haber, D.A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 2007, 7, 169–181. [Google Scholar] [CrossRef] [PubMed]
- Fumarola, C.; Bonelli, M.A.; Petronini, P.G.; Alfieri, R.R. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem. Pharmacol. 2014, 90, 197–207. [Google Scholar] [CrossRef] [PubMed]
- Da Cunha Santos, G.; Shepherd, F.A.; Tsao, M.S. EGFR mutations and lung cancer. Annu. Rev. Pathol. 2011, 6, 49–69. [Google Scholar] [CrossRef] [PubMed]
- Siegelin, M.D.; Borczuk, A.C. Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab. Investig. J. Tech. Methods Pathol. 2014, 94, 129–137. [Google Scholar] [CrossRef] [PubMed]
- Lynch, T.J.; Bell, D.W.; Sordella, R.; Gurubhagavatula, S.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Haserlat, S.M.; Supko, J.G.; Haluska, F.G.; et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004, 350, 2129–2139. [Google Scholar] [CrossRef] [PubMed]
- Paez, J.G.; Janne, P.A.; Lee, J.C.; Tracy, S.; Greulich, H.; Gabriel, S.; Herman, P.; Kaye, F.J.; Lindeman, N.; Boggon, T.J.; et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004, 304, 1497–1500. [Google Scholar] [CrossRef] [PubMed]
- Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L.; et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. USA 2004, 101, 13306–13311. [Google Scholar] [CrossRef] [PubMed]
- Yun, C.H.; Boggon, T.J.; Li, Y.; Woo, M.S.; Greulich, H.; Meyerson, M.; Eck, M.J. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007, 11, 217–227. [Google Scholar] [CrossRef] [PubMed]
- Kumar, A.; Petri, E.T.; Halmos, B.; Boggon, T.J. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J. Clin. Oncol. 2008, 26, 1742–1751. [Google Scholar] [CrossRef] [PubMed]
- Jung, H.J.; Suh, Y. Regulation of IGF-1 signaling by micrornas. Front. Genet. 2014, 5. [Google Scholar] [CrossRef] [PubMed]
- Iams, W.T.; Lovly, C.M. Molecular pathways: Clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clin. Cancer Res. 2015, 21, 4270–4277. [Google Scholar] [CrossRef] [PubMed]
- King, H.; Aleksic, T.; Haluska, P.; Macaulay, V.M. Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer Treat. Rev. 2014, 40, 1096–1105. [Google Scholar] [CrossRef] [PubMed]
- Crudden, C.; Girnita, A.; Girnita, L. Targeting the IGF-1R: The tale of the tortoise and the hare. Front. Endocrinol. 2015, 6. [Google Scholar] [CrossRef] [PubMed]
- Zha, J.; Lackner, M.R. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin. Cancer Res. 2010, 16, 2512–2517. [Google Scholar] [CrossRef] [PubMed]
- Zemva, J.; Schubert, M. Central insulin and insulin-like growth factor-1 signaling: Implications for diabetes associated dementia. Curr. Diabetes Rev. 2011, 7, 356–366. [Google Scholar] [CrossRef] [PubMed]
- O’Neill, C.; Kiely, A.P.; Coakley, M.F.; Manning, S.; Long-Smith, C.M. Insulin and IGF-1 signalling: Longevity, protein homoeostasis and Alzheimer’s disease. Biochem. Soc. Trans. 2012, 40, 721–727. [Google Scholar] [CrossRef] [PubMed]
- Scagliotti, G.V.; Novello, S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat. Rev. 2012, 38, 292–302. [Google Scholar] [CrossRef] [PubMed]
- Park, E.; Park, S.Y.; Kim, H.; Sun, P.L.; Jin, Y.; Cho, S.K.; Kim, K.; Lee, C.T.; Chung, J.H. Membranous insulin-like growth factor-1 receptor (IGF1R) expression is predictive of poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. J. Pathol. Transl. Med. 2015, 49, 382–388. [Google Scholar] [CrossRef] [PubMed]
- Reinmuth, N.; Kloos, S.; Warth, A.; Risch, A.; Muley, T.; Hoffmann, H.; Thomas, M.; Meister, M. Insulin-like growth factor 1 pathway mutations and protein expression in resected non-small cell lung cancer. Hum. Pathol. 2014, 45, 1162–1168. [Google Scholar] [CrossRef] [PubMed]
- Stanilov, N.S.; Karakolev, I.A.; Deliysky, T.S.; Jovchev, J.P.; Stanilova, S.A. Association of insulin-like growth factor-i receptor polymorphism with colorectal cancer development. Mol. Biol. Rep. 2014, 41, 8099–8106. [Google Scholar] [CrossRef] [PubMed]
- Bonafe, M.; Barbieri, M.; Marchegiani, F.; Olivieri, F.; Ragno, E.; Giampieri, C.; Mugianesi, E.; Centurelli, M.; Franceschi, C.; Paolisso, G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: Cues for an evolutionarily conserved mechanism of life span control. J. Clin. Endocrinol. Metab. 2003, 88, 3299–3304. [Google Scholar] [CrossRef] [PubMed]
- Weng, C.J.; Hsieh, Y.H.; Tsai, C.M.; Chu, Y.H.; Ueng, K.C.; Liu, Y.F.; Yeh, Y.H.; Su, S.C.; Chen, Y.C.; Chen, M.K.; et al. Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma. Ann. Surg. Oncol. 2010, 17, 1808–1815. [Google Scholar] [CrossRef] [PubMed]
- Shigematsu, H.; Lin, L.; Takahashi, T.; Nomura, M.; Suzuki, M.; Wistuba, I.I.; Fong, K.M.; Lee, H.; Toyooka, S.; Shimizu, N.; et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J. Natl. Cancer Inst. 2005, 97, 339–346. [Google Scholar] [CrossRef] [PubMed]
- Tokumo, M.; Toyooka, S.; Kiura, K.; Shigematsu, H.; Tomii, K.; Aoe, M.; Ichimura, K.; Tsuda, T.; Yano, M.; Tsukuda, K.; et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin. Cancer Res. 2005, 11, 1167–1173. [Google Scholar] [CrossRef]
- Won, Y.W.; Han, J.Y.; Lee, G.K.; Park, S.Y.; Lim, K.Y.; Yoon, K.A.; Yun, T.; Kim, H.T.; Lee, J.S. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J. Clin. Pathol. 2011, 64, 947–952. [Google Scholar] [CrossRef] [PubMed]
Variable | All Cases (N = 452) n (%) | Adenocarcinoma (N = 362) n (%) | Squamous Cell Carcinoma (N = 90) n (%) | p-Value |
---|---|---|---|---|
Age | ||||
<30 | 3 (0.7%) | 3 (0.8%) | 0 (0%) | p = 0.732 |
30–39 | 9 (2.0%) | 8 (2.2%) | 1 (1.1%) | |
40–49 | 40 (8.8%) | 33 (9.1%) | 7 (7.8%) | |
50–59 | 96 (21.2%) | 80 (22.1%) | 16 (17.8%) | |
60–69 | 99 (21.9%) | 76 (21.0%) | 23 (25.6%) | |
≥70 | 205 (45.4%) | 162 (44.8%) | 43 (47.8%) | |
Mean ± SD | 66.27 ± 13.85 | 65.82 ± 13.95 | 68.06 ± 13.37 | p = 0.171 |
Gender | ||||
Male | 251 (55.5%) | 171 (47.2%) | 80 (88.9%) | p < 0.001 |
Female | 201 (44.5%) | 191 (52.8%) | 10 (11.1%) | |
Cigarette Smoking Status | ||||
Never-smoker | 262 (58.0%) | 242 (66.9%) | 20 (22.2%) | p < 0.001 |
Ever-smoker | 190 (42.0%) | 120 (33.1%) | 70 (77.8%) | |
pack-years | 39.22 ± 29.62 | 33.29 ± 28.80 | 52.95 ± 26.98 | p < 0.001 |
Disease Stage | ||||
IA | 45 (10.0%) | 41 (11.3%) | 4 (4.4%) | p < 0.001 |
IB | 57 (12.6%) | 52 (14.4%) | 5 (5.6%) | |
IIA | 27 (6.0%) | 21 (5.8%) | 6 (6.7%) | |
IIB | 10 (2.2%) | 7 (1.9%) | 3 (3.3%) | |
IIIA | 40 (8.8%) | 29 (8.0%) | 11 (12.2%) | |
IIIB | 67 (14.8%) | 39 (10.8%) | 28 (31.1%) | |
IV | 206 (45.6%) | 173 (47.8%) | 33 (36.7%) | |
Cell Differentiation | ||||
Good | 42 (9.3%) | 39 (10.8%) | 3 (3.3%) | p < 0.001 |
Moderate | 326 (72.1%) | 280 (77.3%) | 46 (51.1%) | |
Poor | 84 (18.6%) | 43 (11.9%) | 41 (45.6%) |
Variable | Adenocarcinoma (N = 362) (%) | Squamous Cell Carcinoma (N = 90) (%) | Odds Ratio (95% Confidence Interval) | Adjusted Odds Ratio (95% CI) |
---|---|---|---|---|
IGF1R rs7166348 | ||||
GG | 117 (32.3%) | 34 (37.8%) | 1.00 | 1.00 |
GA | 189 (52.2%) | 44 (48.9%) | 0.80 (0.48–1.33) | 0.67 (0.39–1.18) |
AA | 56 (15.5%) | 12 (13.3%) | 0.74 (0.36–1.53) | 0.69 (0.31–1.54) |
GA + AA | 245 (67.7%) | 56 (62.2%) | 0.79 (0.49–1.27) | 0.68 (0.40–1.15) |
IGF1R rs2229765 | ||||
GG | 168 (46.4%) | 43 (47.8%) | 1.00 | 1.00 |
GA | 155 (42.8%) | 34 (37.8%) | 0.86 (0.52–1.41) | 0.90 (0.52–1.55) |
AA | 39 (10.8%) | 13 (14.4%) | 1.30 (0.64–2.65) | 2.08 (0.92–4.72) |
GA + AA | 194 (53.6%) | 47 (52.2%) | 0.95 (0.60–1.50) | 1.08 (0.65–1.79) |
IGF1R rs8038415 | ||||
TT | 90 (24.9%) | 27 (30.0%) | 1.00 | 1.00 |
TC | 186 (51.4%) | 37 (41.1%) | 0.66 (0.38–1.16) | 0.61 (0.33–1.13) |
CC | 86 (23.7%) | 26 (28.9%) | 1.01 (0.55–1.86) | 1.02 (0.52–2.03) |
TC + CC | 272 (75.1%) | 63 (70.0%) | 0.77 (0.46–1.29) | 0.73 (0.42–1.29) |
Variable | Wild Type (N = 110) n (%) | L858R (N = 79) n (%) | In-Frame Deletion (N = 81) n (%) | Others (N = 9) n (%) |
---|---|---|---|---|
Age | ||||
<30 | 1 (0.9%) | 0 (0%) | 1 (1.2%) | 0 (0%) |
30–39 | 3 (2.7%) | 0 (0%) | 2 (2.5%) | 0 (0%) |
40–49 | 11 (9.9%) | 6 (7.6%) | 10 (12.3%) | 0 (0%) |
50–59 | 21 (18.9%) | 16 (20.3%) | 27 (33.3%) | 1 (11.1%) |
60–69 | 26 (23.4%) | 16 (20.3%) | 14 (17.3%) | 1 (11.1%) |
≥70 | 49 (44.1%) | 41 (51.9%) | 27 (33.3%) | 7 (77.8%) |
Mean ± SD | 65.36 ± 13.42 | 68.18 ± 12.56 | 62.31 ± 14.01 b | 75.56 ± 9.04 |
Gender | ||||
Male | 67 (60.4%) | 18 (22.8%) a | 38 (46.9%) b | 4 (44.4%) |
Female | 44 (39.6%) | 61 (77.2%) | 43 (53.1%) | 5 (55.6%) |
Cigarette Smoking Status | ||||
Never-smoker | 50 (45.0%) | 70 (88.6%) a | 56 (69.1%) a | 5 (55.6%) |
Ever-smoker | 61 (55.0%) | 9 (11.4%) | 25 (30.9%) | 4 (44.4%) |
PPK | 46.32 ± 28.21 | 12.76 ± 20.81 a | 21.15 ± 23.15 a | 46.00 ± 28.15 |
Disease Stage | ||||
IA | 11 (9.9%) | 6 (7.6%) | 11 (13.6%) | 0 (0%) |
IB | 9 (8.1%) | 13 (16.5%) | 9 (11.1%) | 1 (11.1%) |
IIA | 5 (4.5%) | 4 (5.1%) | 3 (3.7%) | 0 (0%) |
IIB | 1 (0.9%) | 0 (0%) | 0 (0%) | 0 (0%) |
IIIA | 10 (9.0%) | 7 (8.9%) | 4 (4.9%) | 0 (0%) |
IIIB | 17 (15.3%) | 10 (12.7%) | 7 (8.6%) | 2 (22.2%) |
IV | 58 (52.3%) | 39 (49.4%) | 47 (58.0%) | 6 (66.7%) |
Cell Differentiation | ||||
Good | 8 (7.2%) | 11 (13.9%) a | 8 (9.9%) a | 2 (22.2%) |
Moderate | 80 (72.1%) | 63 (79.7%) | 68 (84.0%) | 7 (77.8%) |
Poor | 23 (20.7%) | 5 (6.3%) | 5 (6.1%) | 0 (0%) |
Variable | All Cases (N = 280) | ||
---|---|---|---|
Wild Type (N = 111) (%) | Mutation Type (N = 169) (%) | AOR (95% CI) | |
IGF1R rs7166348 | |||
GG | 36 (32.4%) | 50 (29.6%) | 1.00 |
GA | 59 (53.2%) | 89 (52.7%) | 1.30 (0.72–2.32) |
AA | 16 (14.4%) | 30 (17.7%) | 1.49 (0.67–3.28) |
GA + AA | 75 (67.6%) | 119 (70.4%) | 1.34 (0.77–2.34) |
IGF1R rs2229765 | |||
GG | 48 (43.2%) | 81 (47.9%) | 1.00 |
GA | 50 (45.0%) | 69 (40.8%) | 0.75 (0.43–1.29) |
AA | 13 (11.8%) | 19 (11.3%) | 0.69 (0.29–1.65) |
GA + AA | 63 (56.8%) | 88 (52.1%) | 0.73 (0.44–1.24) |
IGF1R rs8038415 | |||
TT | 29 (26.1%) | 42 (24.9%) | 1.00 |
TC | 51 (45.9%) | 88 (52.1%) | 1.23 (0.66–2.30) |
CC | 31 (27.9%) | 39 (23.0%) | 1.11 (0.54–2.27) |
TC + CC | 80 (73.9%) | 127 (75.1%) | 1.19 (0.66–2.13) |
Male (N = 127) | |||
IGF1R rs7166348 | |||
GG | 21 (31.3%) | 14 (23.3%) | 1.00 |
GA | 38 (56.7%) | 34 (56.7%) | 2.08 (0.63–6.95) |
AA | 8 (12.0%) | 12 (20.0%) | 4.70 (0.90–24.52) |
GA + AA | 46 (68.7%) | 46 (76.7%) | 2.48 (0.99–6.20) |
IGF1R rs2229765 | |||
GG | 35 (43.2%) | 28 (46.7%) | 1.00 |
GA | 26 (45.0%) | 26 (43.3%) | 1.27 (0.57–2.82) |
AA | 6 (11.8%) | 6 (10.0%) | 1.02 (0.25–4.17) |
GA + AA | 32 (47.8%) | 32 (53.3%) | 1.22 (0.57–2.59) |
IGF1R rs8038415 | |||
TT | 16 (23.9%) | 16 (26.7%) | 1.00 |
TC | 34 (50.7%) | 27 (45.0%) | 0.93 (0.36–2.40) |
CC | 17 (25.4%) | 17 (28.3%) | 1.24 (0.44–3.56) |
TC + CC | 51 (76.1%) | 44 (73.3%) | 1.04 (0.43–2.51) |
Female (N = 153) | |||
IGF1R rs7166348 | 15 (34.1%) | 36 (33.0%) | 1.00 |
GG | 21 (47.7%) | 55 (50.5%) | 1.21 (0.53–2.77) |
GA | 8 (18.2%) | 18 (16.5%) | 1.14 (0.37–3.49) |
AA | 29 (65.9%) | 73(67.0%) | 1.19 (0.54–2.60) |
GA + AA | |||
IGF1R rs2229765 | 13 (29.5%) | 53 (48.6%) | 1.00 |
GG | 24 (54.5%) | 43 (39.4%) | 0.35 (0.15–0.82) |
GA | 7 (16.0%) | 13 (12.0%) | 0.54 (0.16–2.85) |
AA | 31 (70.5%) | 56 (51.4%) | 0.39 (0.17–0.87) |
GA + AA | |||
IGF1R rs8038415 | |||
TT | 13 (29.5%) | 26 (23.9%) | 1.00 |
TC | 17 (38.6%) | 61 (55.9%) | 1.61 (0.66–3.97) |
CC | 14 (31.9%) | 22 (20.2%) | 0.84 (0.30–2.35) |
TC + CC | 31 (70.5%) | 83 (76.1%) | 1.30 (0.56–2.98) |
Variable | Wild Type | L858R | Exon 19 in-Frame Deletion | ||
---|---|---|---|---|---|
(N = 44) n (%) | (N = 61) (%) | AOR (95% CI) | (N = 43) (%) | AOR (95% CI) | |
IGF1R rs7166348 | |||||
GG | 15 (34.1%) | 22 (34.1%) | 1.00 | 12 (27.9%) | 1.00 |
GA | 21 (47.7%) | 29 (47.7%) | 1.17 (0.45–3.01) p = 0.746 | 23 (53.5%) | 1.47 (0.53–4.04) p = 0.458 |
AA | 8 (18.2%) | 10 (18.2%) | 1.12 (0.31–4.11) p = 0.864 | 8 (18.6%) | 1.38 (0.36–5.38) p = 0.640 |
GA + AA | 29 (65.9%) | 39 (63.9%) | 1.16 (0.47–2.86) p = 0.751 | 31 (72.1%) | 1.45 (0.55–3.77) p = 0.452 |
IGF1R rs2229765 | |||||
GG | 13 (29.5%) | 34 (55.7%) | 1.00 | 15 (34.9%) | 1.00 |
GA | 24 (54.5%) | 22 (36.1%) | 0.35 (0.14–0.88) p = 0.026 | 21 (48.8%) | 0.53 (0.19–1.49) p = 0.227 |
AA | 7 (16.0%) | 5 (8.2%) | 0.35 (0.08–1.52) p = 0.160 | 7 (16.3%) | 0.85 (0.20–3.66) p = 0.829 |
GA + AA | 31 (70.5%) | 27 (44.3%) | 0.34 (0.14–0.84) p = 0.020 | 28 (65.1%) | 0.58 (0.22–1.58) p = 0.290 |
IGF1R rs8038415 | |||||
TT | 13 (29.5%) | 15 (24.6%) | 1.00 | 10 (23.3%) | 1.00 |
TC | 17 (38.6%) | 33 (54.1%) | 1.77 (0.65–4.85) p = 0.268 | 25 (58.1%) | 1.47 (0.50–4.35) p = 0.484 |
CC | 14 (31.9%) | 13 (21.3%) | 1.00 (0.32–3.16) p = 0.999 | 8 (18.6%) | 0.68 (0.18–2.53) p = 0.560 |
TC + CC | 31 (70.5%) | 46 (75.4%) | 1.45 (0.57–3.66) p = 0.434 | 33 (76.7%) | 1.16 (0.42–3.21) p = 0.780 |
Variable Genotypefrequencies | Clinical Stage | |||
---|---|---|---|---|
N0 + N1 | N2 + N3 | OR (95% CI) | p-Value | |
All Cases (N = 452) | (N = 151) | (N = 185) | ||
IGF1R rs7166348 GG | 68 (45.0%) | 116 (38.5%) | 1.00 | |
GA + AA | 83 (55.0%) | 185 (61.5%) | 1.31 (0.88–1.94) | p = 0.185 |
adenocarcinoma (N = 362) | (N = 117) | (N = 245) | ||
IGF1R rs7166348 GG | 62 (53.0%) | 99 (40.4%) | 1.00 | |
GA + AA | 55 (47.0%) | 146 (59.6%) | 1.66 (1.07–2.59) | p = 0.024 |
Squamous Cell Carcinoma (N = 90) | (N = 34) | (N = 56) | ||
IGF1R rs7166348 GG | 6 (17.6%) | 17 (30.4%) | 1.00 | |
GA + AA | 28 (82.4%) | 39 (69.6%) | 0.49 (0.17–1.40) | p = 0.180 |
Wild Type (N = 111) | (N = 36) | (N = 75) | ||
IGF1R rs7166348 GG | 18 (50.0%) | 20 (26.7%) | 1.00 | |
GA + AA | 18 (50.0%) | 55 (73.3%) | 2.75 (1.20–6.31) | p = 0.015 |
L858R (N = 79) | (N = 28) | (N = 51) | ||
IGF1R rs7166348 GG | 13 (46.4%) | 21 (41.2%) | 1.00 | |
GA + AA | 15 (53.6%) | 30 (58.8%) | 1.24 (0.49–3.13) | p = 0.652 |
In-Frame Deletion (N = 81) | (N = 20) | (N = 61) | ||
IGF1R rs7166348 GG | 5 (25.0%) | 21 (34.4%) | 1.00 | |
GA + AA | 15 (75.0%) | 40 (65.6%) | 0.64 (0.20–1.99) | p = 0.433 |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Liu, T.-C.; Hsieh, M.-J.; Liu, M.-C.; Chiang, W.-L.; Tsao, T.C.-Y.; Yang, S.-F. The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation. Int. J. Mol. Sci. 2016, 17, 763. https://doi.org/10.3390/ijms17050763
Liu T-C, Hsieh M-J, Liu M-C, Chiang W-L, Tsao TC-Y, Yang S-F. The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation. International Journal of Molecular Sciences. 2016; 17(5):763. https://doi.org/10.3390/ijms17050763
Chicago/Turabian StyleLiu, Tu-Chen, Ming-Ju Hsieh, Ming-Che Liu, Whei-Ling Chiang, Thomas Chang-Yao Tsao, and Shun-Fa Yang. 2016. "The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation" International Journal of Molecular Sciences 17, no. 5: 763. https://doi.org/10.3390/ijms17050763