http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, 2014; 34(5): 333–334 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.885052
REVIEW ARTICLE
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by University of Manitoba on 02/17/15 For personal use only.
Association of epidermal growth factor receptor (EGFR) gene polymorphism with lung cancer risk: a systematic review Xu Feng*, Jia-Jin Qin*, Bao-Shi Zheng, Liu-Liu Huang, Xiao-Yong Xie, and Hua-Fu Zhou Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of GuangXi Medical University, NanNing, People’s Republic of China
Abstract
Keywords
Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a well-documented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. In this review, association of EGFR 181946C4T, 8227G4A gene polymorphism with lung cancer was found, and EGFR Short genotype of cytosine adenine repeat number polymorphism was significantly associated with an increased risk of lung cancer.
EGFR, epidermal growth factor receptor, gene polymorphism, systematic review
Introduction Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which consists of four structurally similar, but functionally varied receptors, including erbB1 (HER1/EGFR), erbB2 (HER2/neu), erbB3 (HER3) and erbB4 (HER4) (1). All these transmembrane receptors contain intrinsic kinase activities and are activated by modified tyrosine residues (1). EGFR is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells (2). Agents targeting the EGFR-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers (3). Recent work also suggests that EGFR gene polymorphism might be associated with lung cancer risk. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer causes (4,5). Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a welldocumented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of lung cancer (6–8). *These authors are regarded as joint first authors. Address for correspondence: Hua-Fu Zhou, Department of CardioThoracic Surgery, The First Affiliated Hospital of GuangXi Medical University, NanNing 530021, People’s Republic of China. E-mail: [email protected]
History Received 30 December 2013 Revised 14 January 2014 Accepted 15 January 2014 Published online 4 February 2014
The factor of gene polymorphism has been shown to affect protein activity and in various diseases associated with the development of degenerate cellular mechanisms. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. Relevant studies were extracted from the electronic databases of PubMed, Cochrane Library on 1 October 2013. The retrieval strings entered into these databases were: ‘‘(epidermal growth factor receptor OR EGFR) AND (lung cancer) AND (polymorphism OR variant)’’. Association of EGFR 181946C4T gene polymorphism with lung cancer Five polymorphisms (127378C4T, 142285G4A, 162093G4A, 181946C4T and 187114T4C) were genotyped in 582 lung cancer patients and in 582 healthy controls by Choi et al. (9), and reported that 181946C4T genotype distribution was significantly different between the cases and controls. Compared with the 181946 CC + CT genotype, the 181946 TT genotype was associated with a significantly decreased risk of lung cancer; however, the association for other polymorphisms was not found. The sample size in this study was a little large, and the conclusion might be robust to some extent. Association of EGFR 8227G4A gene polymorphism with lung cancer Jou et al. (10) conducted a matched case-control study of 730 lung cancer patients and 730 healthy controls for examining
334
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the association in Taiwanese population, and 14 tag SNPs (rs4947963, rs763317, rs2302534, rs917880, rs11977660, rs3778866, rs12671550, rs12668175, rs2072454, rs12718946, rs3735059, rs2017000, rs2075108 and rs2280653) distributed in EGFR were selected for genotyping and one SNP 8227G4A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by University of Manitoba on 02/17/15 For personal use only.
Association of EGFR cytosine adenine repeat number polymorphism with lung cancer The cytosine adenine (CA) repeat number polymorphism in the first intron of EGFR has been shown to be inversely correlated with EGFR production. Yoshida et al. (11) carried out a case-cohort study within the Japanese atomic bomb (A-bomb) survivor cohort to evaluate a possible association of CA repeat polymorphism with lung cancer risk, and by dividing study subjects into Short and Long genotypes, defined as the summed CA repeat number of two alleles 5 or ¼ 37 and 4 or ¼ 38, respectively, and they found that the Short genotype was significantly associated with an increased risk of lung cancer, specifically adenocarcinoma.
Discussion In this systematic review, there was three reports were included to explore the association of EGFR 8227G4A gene polymorphism with lung cancer. Association of EGFR 181946C4T, 8227G4A gene polymorphism with lung cancer was found, and EGFR Short genotype of CA repeat number polymorphism was significantly associated with an increased risk of lung cancer. More studies on the relationship between EGFR gene polymorphism and lung cancer risk should be performed in the future. There were studies reported that EGFR gene polymorphism was associated with lung cancer progression. Guo et al. (12) investigated whether 216G/T (rs712829), a functional polymorphism of the EGFR promoter that was able to induce EGFR activation and overexpression, was associated with the pleural metastasis of lung adenocarcinoma, and reported that the frequencies of allele T and genotypes G/T and T/T in the pleural metastasis group were significantly higher compared with those in the non-metastasis group. Dong et al. (13) studied the polymorphism in EGFR gene had been identified to be associated with cancer survival, and reported that subjects carrying EGFR rs3735061 AA and rs6958497 AG/GG genotypes survived significantly shorter time than
J Recept Signal Transduct Res, 2014; 34(5): 333–334
those carrying rs3735061 AG/GG and rs6958497 AA. However, subjects carrying EGFR rs759165 AG/AA genotypes survived significantly longer than those carrying rs759165GG genotype. Well-designed studies with larger size should be conducted in the future to confirm the association of EGFR gene polymorphism with lung cancer, such Genome Wide Association Studies.
Declaration of interest The authors report no conflicts of interests.
References 1. Aydin K, Okutur SK, Bozkurt M, et al. Effect of epidermal growth factor receptor status on the outcomes of patients with metastatic gastric cancer: a pilot study. Oncol Lett 2014;7:255–9. 2. Voldborg BR, Damstrup L, Spang-Thomsen M, et al. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197–206. 3. Mahipal A, Kothari N, Gupta S. Epidermal growth factor receptor inhibitors: coming of age. Cancer Control 2014;21:74–9. 4. Krishnamurthy A, Vijayalakshmi R, Gadigi V, et al. The relevance of ‘‘Nonsmoking-associated lung cancer’’ in India: a single-centre experience. Indian J Cancer 2012;49:82–8. 5. Ada AO, Kunak SC, Hancer F, et al. Association between GSTM1, GSTT1, and GSTP1 polymorphisms and lung cancer risk in a Turkish population. Mol Biol Rep 2012;39:5985–93. 6. Yin J, Li Y, Yin M, et al. TERT-CLPTM1L polymorphism rs401681 contributes to cancers risk: evidence from a meta-analysis based on 29 publications. PLoS One 2012;7:e50650. 7. Chen YB, Mu CY, Chen C, et al. Association between single nucleotide polymorphism of PD-L1 gene and non-small cell lung cancer susceptibility in a Chinese population. Asia Pac J Clin Oncol 2012. [Epub ahead of print]. 8. Wang X, Cui E, Zeng H, et al. RAGE genetic polymorphisms are associated with risk, chemotherapy response and prognosis in patients with advanced NSCLC. PLoS One 2012;7:e43734. 9. Choi JE, Park SH, Kim KM, et al. Polymorphisms in the epidermal growth factor receptor gene and the risk of primary lung cancer: a case-control study. BMC Cancer 2007;7:199. 10. Jou YS, Lo YL, Hsiao CF, et al. Association of an EGFR intron 1 SNP with never-smoking female lung adenocarcinoma patients. Lung Cancer 2009;64:251–6. 11. Yoshida K, Nakachi K, Imai K, et al. Lung cancer susceptibility among atomic bomb survivors in relation to CA repeat number polymorphism of epidermal growth factor receptor gene and radiation dose. Carcinogenesis 2009;30:2037–41. 12. Guo H, Xing Y, Liu R, et al. 216G/T (rs712829), a functional variant of the promoter, is associated with the pleural metastasis of lung adenocarcinoma. Oncol Lett 2013;6:693–8. 13. Dong J, Dai J, Shu Y, et al. Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population. Carcinogenesis 2010;31:1080–6.
REVIEW ARTICLE
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by University of Manitoba on 02/17/15 For personal use only.
Association of epidermal growth factor receptor (EGFR) gene polymorphism with lung cancer risk: a systematic review Xu Feng*, Jia-Jin Qin*, Bao-Shi Zheng, Liu-Liu Huang, Xiao-Yong Xie, and Hua-Fu Zhou Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of GuangXi Medical University, NanNing, People’s Republic of China
Abstract
Keywords
Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a well-documented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. In this review, association of EGFR 181946C4T, 8227G4A gene polymorphism with lung cancer was found, and EGFR Short genotype of cytosine adenine repeat number polymorphism was significantly associated with an increased risk of lung cancer.
EGFR, epidermal growth factor receptor, gene polymorphism, systematic review
Introduction Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which consists of four structurally similar, but functionally varied receptors, including erbB1 (HER1/EGFR), erbB2 (HER2/neu), erbB3 (HER3) and erbB4 (HER4) (1). All these transmembrane receptors contain intrinsic kinase activities and are activated by modified tyrosine residues (1). EGFR is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells (2). Agents targeting the EGFR-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers (3). Recent work also suggests that EGFR gene polymorphism might be associated with lung cancer risk. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer causes (4,5). Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a welldocumented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of lung cancer (6–8). *These authors are regarded as joint first authors. Address for correspondence: Hua-Fu Zhou, Department of CardioThoracic Surgery, The First Affiliated Hospital of GuangXi Medical University, NanNing 530021, People’s Republic of China. E-mail: [email protected]
History Received 30 December 2013 Revised 14 January 2014 Accepted 15 January 2014 Published online 4 February 2014
The factor of gene polymorphism has been shown to affect protein activity and in various diseases associated with the development of degenerate cellular mechanisms. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. Relevant studies were extracted from the electronic databases of PubMed, Cochrane Library on 1 October 2013. The retrieval strings entered into these databases were: ‘‘(epidermal growth factor receptor OR EGFR) AND (lung cancer) AND (polymorphism OR variant)’’. Association of EGFR 181946C4T gene polymorphism with lung cancer Five polymorphisms (127378C4T, 142285G4A, 162093G4A, 181946C4T and 187114T4C) were genotyped in 582 lung cancer patients and in 582 healthy controls by Choi et al. (9), and reported that 181946C4T genotype distribution was significantly different between the cases and controls. Compared with the 181946 CC + CT genotype, the 181946 TT genotype was associated with a significantly decreased risk of lung cancer; however, the association for other polymorphisms was not found. The sample size in this study was a little large, and the conclusion might be robust to some extent. Association of EGFR 8227G4A gene polymorphism with lung cancer Jou et al. (10) conducted a matched case-control study of 730 lung cancer patients and 730 healthy controls for examining
334
X. Feng et al.
the association in Taiwanese population, and 14 tag SNPs (rs4947963, rs763317, rs2302534, rs917880, rs11977660, rs3778866, rs12671550, rs12668175, rs2072454, rs12718946, rs3735059, rs2017000, rs2075108 and rs2280653) distributed in EGFR were selected for genotyping and one SNP 8227G4A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by University of Manitoba on 02/17/15 For personal use only.
Association of EGFR cytosine adenine repeat number polymorphism with lung cancer The cytosine adenine (CA) repeat number polymorphism in the first intron of EGFR has been shown to be inversely correlated with EGFR production. Yoshida et al. (11) carried out a case-cohort study within the Japanese atomic bomb (A-bomb) survivor cohort to evaluate a possible association of CA repeat polymorphism with lung cancer risk, and by dividing study subjects into Short and Long genotypes, defined as the summed CA repeat number of two alleles 5 or ¼ 37 and 4 or ¼ 38, respectively, and they found that the Short genotype was significantly associated with an increased risk of lung cancer, specifically adenocarcinoma.
Discussion In this systematic review, there was three reports were included to explore the association of EGFR 8227G4A gene polymorphism with lung cancer. Association of EGFR 181946C4T, 8227G4A gene polymorphism with lung cancer was found, and EGFR Short genotype of CA repeat number polymorphism was significantly associated with an increased risk of lung cancer. More studies on the relationship between EGFR gene polymorphism and lung cancer risk should be performed in the future. There were studies reported that EGFR gene polymorphism was associated with lung cancer progression. Guo et al. (12) investigated whether 216G/T (rs712829), a functional polymorphism of the EGFR promoter that was able to induce EGFR activation and overexpression, was associated with the pleural metastasis of lung adenocarcinoma, and reported that the frequencies of allele T and genotypes G/T and T/T in the pleural metastasis group were significantly higher compared with those in the non-metastasis group. Dong et al. (13) studied the polymorphism in EGFR gene had been identified to be associated with cancer survival, and reported that subjects carrying EGFR rs3735061 AA and rs6958497 AG/GG genotypes survived significantly shorter time than
J Recept Signal Transduct Res, 2014; 34(5): 333–334
those carrying rs3735061 AG/GG and rs6958497 AA. However, subjects carrying EGFR rs759165 AG/AA genotypes survived significantly longer than those carrying rs759165GG genotype. Well-designed studies with larger size should be conducted in the future to confirm the association of EGFR gene polymorphism with lung cancer, such Genome Wide Association Studies.
Declaration of interest The authors report no conflicts of interests.
References 1. Aydin K, Okutur SK, Bozkurt M, et al. Effect of epidermal growth factor receptor status on the outcomes of patients with metastatic gastric cancer: a pilot study. Oncol Lett 2014;7:255–9. 2. Voldborg BR, Damstrup L, Spang-Thomsen M, et al. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197–206. 3. Mahipal A, Kothari N, Gupta S. Epidermal growth factor receptor inhibitors: coming of age. Cancer Control 2014;21:74–9. 4. Krishnamurthy A, Vijayalakshmi R, Gadigi V, et al. The relevance of ‘‘Nonsmoking-associated lung cancer’’ in India: a single-centre experience. Indian J Cancer 2012;49:82–8. 5. Ada AO, Kunak SC, Hancer F, et al. Association between GSTM1, GSTT1, and GSTP1 polymorphisms and lung cancer risk in a Turkish population. Mol Biol Rep 2012;39:5985–93. 6. Yin J, Li Y, Yin M, et al. TERT-CLPTM1L polymorphism rs401681 contributes to cancers risk: evidence from a meta-analysis based on 29 publications. PLoS One 2012;7:e50650. 7. Chen YB, Mu CY, Chen C, et al. Association between single nucleotide polymorphism of PD-L1 gene and non-small cell lung cancer susceptibility in a Chinese population. Asia Pac J Clin Oncol 2012. [Epub ahead of print]. 8. Wang X, Cui E, Zeng H, et al. RAGE genetic polymorphisms are associated with risk, chemotherapy response and prognosis in patients with advanced NSCLC. PLoS One 2012;7:e43734. 9. Choi JE, Park SH, Kim KM, et al. Polymorphisms in the epidermal growth factor receptor gene and the risk of primary lung cancer: a case-control study. BMC Cancer 2007;7:199. 10. Jou YS, Lo YL, Hsiao CF, et al. Association of an EGFR intron 1 SNP with never-smoking female lung adenocarcinoma patients. Lung Cancer 2009;64:251–6. 11. Yoshida K, Nakachi K, Imai K, et al. Lung cancer susceptibility among atomic bomb survivors in relation to CA repeat number polymorphism of epidermal growth factor receptor gene and radiation dose. Carcinogenesis 2009;30:2037–41. 12. Guo H, Xing Y, Liu R, et al. 216G/T (rs712829), a functional variant of the promoter, is associated with the pleural metastasis of lung adenocarcinoma. Oncol Lett 2013;6:693–8. 13. Dong J, Dai J, Shu Y, et al. Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population. Carcinogenesis 2010;31:1080–6.
