BAX G(-248)A Gene Polymorphism and Its Association with Risk of Non-Small Cell Lung Cancer—A Case Control Study

Read  full  paper  at:http://www.scirp.org/journal/PaperInformation.aspx?PaperID=56019

ABSTRACT

Pro-apoptotic Bcl-2 protein BAX is an important member of mitochondrial dependent apoptosis regulation and ultimately plays a pivotal role in malignancies. A promoter G(-248)A polymorphism in the TP53 binding region of BAX results in differential binding capacity of TP53 protein there by regulating its expression, which has been found to be associated with different clinical outcomes in various malignancies. Presently we aimed to analyze the possible impact of the BAX G(-248)A polymorphism on the risk and other clinical features of non-small cell lung cancer in Indian population. The BAX promoter polymorphism was analyzed in blood samples of 320 subjects with 1:1 case/control ratio by primer-introduced restriction analysis PCR and survival curves were plotted using Kaplan-Meier analysis. It was observed that more than 3-fold increased risk of developing non-small cell lung cancer was associated with homozygous AA genotype of BAX G(-248)A promoter polymorphism in Indian population, with more predominant in smokers with pack-year > 45 (heavy) and using cigarette or huka as their smoking source than homozygous GG genotype. Significant associations was observed between TNM stage (p = 0.037) and histological type (0.02), of non-small cell lung cancer patients with the polymorphism. Patients homozygous for A allele exhibited a significant poor overall survival compared with patients displaying GA + AA or GA or GG genotype [median survival 6.0 vs 9.0, 11.0, and 30.0 months, respectively (p < 0.0001)]. Adenocarcinoma and advanced stage patients with AA genotype showed lower median survival time than squamous cell carcinoma and early stage non-small cell lung cancer patients (median 3.0 and 5.0 vs 8.0 and 9.0 months, respectively). We conclude that the genetic polymorphism G(-248)A in the TP53 binding promoter region of pro-apoptotic genes BAX may contribute to the risk of developing non-small cell lung cancer in Indian population and also may be an important factor for adverse clinical outcome for patients with non-small cell lung cancer.

Cite this paper

Javid, J. , Mir, R. , Julka, P. , Ray, P. and Saxena, A. (2015) BAX G(-248)A Gene Polymorphism and Its Association with Risk of Non-Small Cell Lung Cancer—A Case Control Study. Open Journal of Apoptosis, 4, 47-58. doi: 10.4236/ojapo.2015.42005.

References

[1] Parkin, D.M., Bray, F., Ferlay, J. and Pisani, P. (2005) Global Cancer Statistics, 2002. CA: A Cancer Journal for Clinicians, 55, 74-108. http://dx.doi.org/10.3322/canjclin.55.2.74
[2] Dikshit, R., Gupta, P.C., Ramasundarahettige, C., Gajalakshmi, V., Aleksandrowicz, L., Badwe, R., et al. (2012) Cancer Mortality in India: A Nationally Representative Survey. Lancet, 379, 1807-1816.
http://dx.doi.org/10.1016/S0140-6736(12)60358-4
[3] Kasper, D.L., Braunwald, E., Hauser, S., Longo, D., Jameson, J.L. and Fauci, A.S. (2005) Neoplasms of the Lung, Harrison’s Principles of Internal Medicine. 16th Edition, 506-515.
[4] Levi, F. (1999) Cancer Prevention: Epidemiology and Perspectives. European Journal of Cancer, 35, 1912-1924. http://dx.doi.org/10.1016/S0959-8049(99)00294-4
[5] Schottenfeld, D. and Fraumeni, J.F. (2006) Cancer Epidemiology and Prevention. 3rd Edition, 638-658. http://dx.doi.org/10.1093/acprof:oso/9780195149616.001.0001
[6] Salgia, R. and Skarin, A.T. (1998) Molecular Abnormalities in Lung Cancer. Journal of Clinical Oncology, 16, 1207- 1217.
[7] Thompson, C.B. (1995) Apoptosis in the Pathogenesis and Treatment of Disease. Science, 267, 1456-1462. http://dx.doi.org/10.1126/science.7878464
[8] Gross, A., McDonnell, J.M. and Korsmeyer, S.J. (1999) BCL-2 Family Members and the Mitochondria in Apoptosis. Genes Development, 13, 1899-1911. http://dx.doi.org/10.1101/gad.13.15.1899
[9] Starczynski, J., Pepper, C., Pratt, G., Hooper, L., Thomas, A., Milligan, D., et al. (2005) Common Polymorphism G(-248)A in the Promoter Region of the Bax Gene Results in Significantly Shorter Survival in Patients with Chronic Lymphocytic Leukemia Once Treatment Is Initiated. Journal of Clinical Oncology, 23, 1514-1521. http://dx.doi.org/10.1200/JCO.2005.02.192
[10] Ocana, M.G., Valle-Garay, E., Montes, A.H., Meana, A., Carton, J.A., Fierer, J., et al. (2007) Bax Gene G(-248)A Promoter Polymorphism Is Associated with Increased Lifespan of the Neutrophils of Patients with Osteomyelitis. Genetics in Medicine, 9, 249-255.
http://dx.doi.org/10.1097/GIM.0b013e318039b23d
[11] Chen, K., Hu, Z., Wang, L.E., Sturgis, E.M., El-Naggar, A.K., Zhang, W. and Wei, Q. (2007) Single-Nucleotide Polymorphisms at the TP53-Binding or Responsive Promoter Regions of BAX and BCL2 Genes and Risk of Squamous Cell Carcinoma of the Head and Neck. Carcinogenesis, 28, 2008-2012. http://dx.doi.org/10.1093/carcin/bgm172
[12] Yu, D.K., Guo, Y.L., Tan, W. and Lin, D.X. (2010) Functional BAX Polymorphism Associated with Lung Cancer Susceptibility. Chinese Journal of Oncology, 32, 324-327.
[13] Fegan, C., Starczynski, J., Pratt, G. and Pepper, C. (2006) The Role of the Bax Gene Polymorphism G(-248)A in Chronic Lymphocytic Leukemia. Leukemia, 20, 1460-1461.
http://dx.doi.org/10.1038/sj.leu.2404280
[14] Nuckel, H., Frey, U.H., Sellmann, L., Bau, M., Durig, J., Dührsen, U. and Siffert, W. (2006) Bax Gene G(-248)A Promoter Polymorphism and Chronic Lymphocytic Leukemia: Lack of Association with Incidence, Disease Stage and Progression-Free Survival. Leukemia, 20, 724.
[15] Moshynska, O., Sankaran, K. and Saxena, A. (2003) Molecular Detection of the G(-248) A BAX Promoter Nucleotide Change in B Cell Chronic Lymphocytic Leukaemia. Molecular Pathology, 56, 205-209.
http://dx.doi.org/10.1136/mp.56.4.205
[16] Saxena, A., Moshynska, O., Sankaran, K., Viswanathan, S. and Sheridan, D.P. (2002) Association of a Novel Single Nucleotide Polymorphism, G(-248)A, in the UTR of BAX Gene in Chronic Lymphocytic Leukemia with Disease Progression and Treatment Resistance. Cancer Letters, 187, 199-205. http://dx.doi.org/10.1016/S0304-3835(02)00378-6
[17] Skogsberg, S., Tobin, G., Kröber, A., Kienle, D., Thunberg, U., Aleskog, A., et al. (2006) The G(-248)A Polymorphism in the Promoter Region of the Bax Gene Does Not Correlate with Prognostic Markers or Overall Survival in Chronic Lymphocytic Leukemia. Leukemia, 20, 77-81.
http://dx.doi.org/10.1038/sj.leu.2404030
[18] Hu, Z.B., Li, C.Y., Chen, K.X., Wang, L.E., Sturgis, E.M., Spitz, M.R. and Wei, Q.Y. (2008) Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis. Journal of Cancer Epidemiology, 2008, Article ID: 147905. http://dx.doi.org/10.1155/2008/147905
[19] Jeong, S.H., Lee, H.W., Han, J.H., Kang, S.Y., Choi, J.H., Jung, Y.M., et al. (2008) Low Expression of Bax Predicts Poor Prognosis in Resected Non-Small Cell Lung Cancer Patients with Non-Squamous Histology. Japanese Journal of Clinical Oncology, 38, 661-669. http://dx.doi.org/10.1093/jjco/hyn089
[20] Porebska, I., Wyrodek, E., Kosacka, M., Adamiak, J., Jankowska, R. and Harlozińska-Szmyrka, A. (2006) Apoptotic Markers p53, Bcl-2 and Bax in Primary Lung Cancer. In Vivo, 20, 599-604.
[21] Thornborrow, E.C., Patel, S., Mastropietro, A.E., Schwartzfarb, E.M. and Manfredi, J.J. (2002) A Conserved Intronic Response Element Mediates Direct p53-Dependent Transcriptional Activation of Both the Human and Murine Bax Genes. Oncogene, 21, 990-999. http://dx.doi.org/10.1038/sj.onc.1205069
[22] Miyashita, T. and Reed, J.C. (1995) Tumor Suppressor p53 Is a Direct Transcriptional Activator of the Human Bax Gene. Cell, 80, 293-299. http://dx.doi.org/10.1016/0092-8674(95)90412-3
[23] Mori, S., Ito, G., Shimokata, K. and Sekido, Y. (2004) p53 Apoptotic Pathway Molecules Are Frequently and Simultaneously Altered in Non small Cell Lung Carcinoma. Cancer, 100, 1673-1682.
http://dx.doi.org/10.1002/cncr.20164
[24] Kang, S.Y., Han, J.H., Lee, K.J., Choi, J.H., Park, J.I., Kim, H.I., et al. (2007) Low Expression of Bax Predicts Poor Prognosis in Patients with Locally Advanced Esophageal Cancer Treated with Definitive Chemoradiotherapy. Clinical Cancer Research, 13, 4146-4153.
http://dx.doi.org/10.1158/1078-0432.CCR-06-3063
[25] Milas, I., Komaki, R., Hachiya, T., Bubb, R.S., Ro, J.Y., Langford, L., et al. (2003) Epidermal Growth Factor Receptor, Cyclooxygenase-2, and BAX Expression in the Primary Non-Small Cell Lung Cancer and Brain Metastases. Clinical Cancer Research, 9, 1070-1076.
[26] Gessner, C., Liebers, U., Kuhn, H., Stiehl, P., Witt, C., Schauer, J. and Wolff, G. (2002) BAX and p16INK4A Are Independent Positive Prognostic Markers for Advanced Tumour Stage of Nonsmall Cell Lung Cancer. European Respiratory Journal, 19, 134-140. http://dx.doi.org/10.1183/09031936.02.00219402
[27] Sakakura, C., Sweeney, E.A., Shirahama, T., Igarashi, Y., Hakomori, S., Tsujimoto, H., et al. (1997) Over Expression of Bax Sensitizes Breast Cancer Mcf-7 Cells to Cisplatin and Etoposide. Surgery Today, 27, 676-679. http://dx.doi.org/10.1007/BF02388231
[28] Biagosch, J., Huber, R.M. and Bergner, A. (2010) Reduced Expression of BAX in Small Cell Lung Cancer Cells Is Not Sufficient to Induce Cisplatin-Resistance. European Journal of Medical Research, 15, 448-451. http://dx.doi.org/10.1186/2047-783X-15-10-448
[29] Gibson, L.F., Fortney, J., Magro, G., Ericson, S.G., Lynch, J.P. and Landreth, K.S. (1999) Regulation of Bax and Bcl-2 Expression in Breast Cancer Cells by Chemotherapy. Breast Cancer Research and Treatment, 55, 107-117.
[30] Tsuji, T., Noguchi, M., Kido, Y., Kubota, H., Takemura, K., Nakamori, K. and Hiratsuka, H. (2007) Predictive Assay of Neoadjuvant Chemotherapy in Management of Oral Cancer. International Journal of Oral and Maxillofacial Surgery, 36, 15-19. http://dx.doi.org/10.1016/j.ijom.2006.10.009
Advertisements

发表评论

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / 更改 )

Twitter picture

You are commenting using your Twitter account. Log Out / 更改 )

Facebook photo

You are commenting using your Facebook account. Log Out / 更改 )

Google+ photo

You are commenting using your Google+ account. Log Out / 更改 )

Connecting to %s