Sains Malaysiana 47(1)(2018): 141–148

http://dx.doi.org/10.17576/jsm-2018-4701-17

 

STK15 Phe31Ile and Val57Ile Polymorphisms Increase the Risk of Gastrointestinal Cancer

(Polimorfisme STK15 Phe31Ile dan Val57Ile Meningkatkan Risiko terhadap Kanser Gastrousus)

 

TIANXIN LAI1, ERIC TZYY JIANN CHONG1, JITT AUN CHUAH2, KEK HENG CHUA3 & PING-CHIN LEE1*

 

1Biotechnology Programme, Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Jalan UMS, 88400 Kota Kinabalu, Sabah Negeri di Bawah Bayu, Malaysia

 

2Surgery Department, Queen Elizabeth Hospital, Jalan Penampang, 88200 Kota Kinabalu, Sabah Negeri di Bawah Bayu, Malaysia

 

3Department of Biomedical Science, Faculty of Medicine Building, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

Diserahkan: 15 Januari 2016/Diterima: 3 Jun 2017

 

ABSTRACT

STK15 is a serine/threonine kinase that regulates chromosomal segregation during mitosis. Single nucleotide polymorphisms (SNPs) in this gene, Phe31Ile (rs2273535) and Val57Ile (rs1047972), are inconsistently associated with gastrointestinal cancer (GIC) across different populations. However, this association is unclear in Malaysian population. Therefore, this study investigated the association of STK15 Phe31Ile and Val57Ile polymorphisms to GIC risk in Malaysia. Genomic DNA was extracted from 185 GIC patients and 1110 healthy controls and was subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. SNPs were further confirmed using sequencing. We found that the 31Phe allele and 31Phe/Phe genotype in the Phe31Ile SNP significantly increased GIC risk in Malaysian population, particularly in gastric cancer (p<0.017). The combined analysis for both SNPs also increased the risk of GIC in this study. Etiological factors such as age, gender and ethnicity were not associated with GIC in the population. This is the first study to report the association of STK15 Phe31Ile and Val57Ile SNPs with an increased risk of GIC in Malaysians; the 31Phe allele is exclusively associated with the risk of gastric cancer. In addition, GIC incidences among Malaysians have significantly shifted to a younger age (<50 years).

 

Keywords: Gastrointestinal cancer; Malaysian population; STK15 polymorphisms

 

ABSTRAK

STK15 adalah kinase serin/treonina yang mengawal perpisahan kromosom semasa mitosis. Polimorfisme nukleotida tunggal (SNPs) pada gen ini, Phe31Ile (rs2273535) dan Val57Ile (rs1047972) adalah dikaitkan dengan kanser gastrousus (GIC) secara tidak tekal dalam populasi yang berbeza. Walau bagaimanapun, perkaitan tersebut adalah tidak jelas di dalam populasi di Malaysia. Oleh itu, penyelidikan ini mengkaji perkaitan bagi polimorfisme STK15 Phe31Ile dan Val57Ile terhadap risiko GIC di Malaysia. DNA genom diekstrak daripada 185 pesakit GIC dan 1110 kawalan yang sihat. Seterusnya, analisis tindak balas berantai polimerase pemotongan panjang cebisan (PCR-RFLP) dijalankan dan SNP turut disahkan dengan menggunakan teknik penjujukan DNA. Kami mendapati bahawa alel 31Phe dan genotip 31Phe/Phe dalam SNP Phe31Ile meningkatkan risiko terhadap GIC dalam populasi di Malaysia secara signifikan, terutamanya dalam kanser gastrik (p<0.017). Analisis gabungan bagi kedua-dua SNP juga meningkatkan risiko terhadap GIC dalam kajian ini. Faktor etiologi seperti umur, jantina dan etnik adalah tidak berkait dengan GIC dalam populasi ini. Kajian ini merupakan kajian pertama yang melaporkan tentang perkaitan antara SNP STK15 Phe31Ile dan Val57Ile dengan peningkatan risiko terhadap GIC di Malaysia; terutamanya alel 31Phe yang dikaitkan dengan risiko kanser gastrik. Selain itu, kejadian GIC dalam kalangan rakyat Malaysia telah beralih secara signifikan kepada usia yang lebih muda (<50 tahun).

 

Kata kunci: Kanser gastrousus; polimorfisme STK15; populasi Malaysia

RUJUKAN

Bischoff, J.R., Anderson, L., Zhu, Y., Mossie, K., Ng, L., Souza, B., Schryver, B., Flanagan, P., Clairvoyant, F., Ginther, C., Chan, C.S., Novotny, M., Slamon, D.J. & Plowman, G.D. 1998. A homologue of drasophila Aurora kinase is oncogenic and amplified in human colorectal cancer. EMBO Journal 17: 3062-3065.

Chen, G.L., Hou, G.L., Sun, F., Jiang, H.L., Xue, J.F., Li, X.S., Xu, E.H., Gao, W.S. & Cao, J.P. 2014. Upregulation of STK15 in esophageal squamous cell carcinomas in a Mongolian population. Asian Pacific Journal of Cancer Prevention 15: 6021-6024.

Chen, J., Li, D., Wei, C., Sen, S., Killary, A.M., Amos, C.I., Evans, D.B., Abbruzzese, J.L. & Frazier, M.L. 2007. Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasian. Clinical Cancer Research 13: 3100-3104.

Cheng, J.L., Randall, A. & Baldi, P. 2006. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins: Structure, Function and Bioinformatics 62: 1125-1132.

Chong, E.T.J., Goh, L.P.W., See, E.U.H., Chuah, J.A., Chua, K.H. & Lee, P.C. 2016. Association of CYP2E1, STK15 and XRCC1 polymorphisms with risk of breast cancer in Malaysia women. Asian Pacific Journal of Cancer Prevention 17: 647-653.

Chong, E.T.J., Lee, C.C., Chua, K.H., Chuah, J.A. & Lee, P.C. 2014. RsaI but not DraI polymorphism in CYP2E1 gene increases the risk of gastrointestinal cancer in Malaysians: A case-control study. BMJ Open 4: e004109.

Dai, Q., Cai, Q.Y., Shu, X.O., Ewart-Toland, A., Wen, W.Q., Balmain, A., Gao, Y.T. & Zheng, W. 2004. Synergistic effects of STK15 gene polymorphisms and endogenous estrogen exposure in the risk of breast cancer. Cancer Epidemiology, Biomarkers & Prevention 13: 2065-2070.

Dai, Z.J., Kang, H.F., Wang, X.J., Shao, Y.P., Lin, S., Zhao, Y., Ren, H.T., Min, W.L., Wang, M. & Liu, X.X. 2014. Association between genetic polymorphisms in AURKA (rs2273535 and rs1047972) and breast cancer risk: A meta-analysis involving 37,221 subjects. Cancer Cell International 14: 91.

Department of Health Statistics. 2013. Health Indicators 2005- 2010. Kuala Lumpur: Ministry of Health Press. p. 98.

Dogan, I., Ekmekci, A., Yurdakul, A.S., Onen, I.H., Ozturk, C., Cirak, M.Y., Acar, A. & Konac, E. 2008. Polymorphism in the Aurora-A gene is not associated with lung cancer in the Turkish population. DNA and Cell Biology 27: 443-448.

Dutertre, S., Descamps, S. & Prigent, C. 2002. On the role of aurora-A in centrosome function. Oncogene 21: 6175-6183.

Ewart-Toland, A., Dai, Q., Gao, Y.T., Nagase, H., Dunlop, M.G., Farrington, S.M., Barnetson, R.A., Anton-Culver, H., Peel, D., Ziogas, A., Lin, D., Miao, X., Sun, T., Ostrander, E.A., Stanford, J.L., Langlois, M., Chan, J.M., Yuan, J., Harris, C.C., Bowman, E.D., Clayman, G.L., Lippman, S.M., Lee, J.J., Zheng, W. & Balmain, A. 2005. Aurora-a/STK15 T+91A is a general low penetrance cancer susceptibility gene: A meta-analysis of multiple cancer types. Carcinogenesis 26: 1368-1373.

Ewart-Toland, A., Briassouli, P., de Koning, J.P., Mao, J.H., Yuan, J., Chan, F., MacCarthy-Morrogh, L., Ponder, B.A., Nagase, H., Burn, J., Ball, S., Almeida, M., Linardopoulos, S. & Balmain, A. 2003. Identification of STK6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nature Genetics 34: 403-412.

Gu, J., Gong, Y., Huang, M., Lu, C., Spitz, M.R. & Wu, X. 2007. Polymorphism of STK15 (Aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis 28: 350-355.

Honda, K., Mihara, H., Kato, Y., Yamaguchi, A., Tanaka, H., Yasuda, H., Furukawa, K. & Urano, T. 2000. Degradation of human Aurora 2 protein kinase by the anaphase promoting complex-ubiquitin-proteasome pathway. Oncogene 19: 2812-2819.

International Agency for Research on Cancer. 2014. World Cancer Report 2014. Geneva: World Health Organization Press. pp. 374-421.

Ju, H., Cho, H., Kim, Y.S., Kim, W.H., Ihm, C., Noh, S.M., Kim, J.B., Hahn, D.S., Choi, B.Y. & Kang, C. 2006. Functional polymorphism 57Val>Ile of Aurora kinase A associated with increased risk of gastric cancer progression. Cancer Letters 242: 273-279.

Kimura, M.T., Mori, T., Conroy, J., Nowak, N.J., Satomi, S., Tamai, K. & Nagase, H. 2005. Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk. Cancer Research 65: 3548- 3554.

Malaysian Gastro-Intestinal Registry. 2009. 1st Report 2009: Include Endoscopic Procedures from National Endoscopy Registry. Kuala Lumpur: Clinical Research Centre Press. pp. 17-22.

Miao, X., Sun, T., Wang, Y., Zhang, X., Tan, W. & Lin, D. 2004. Functional STK15 Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma. Cancer Research 64: 2680-2683.

Pan, J.Y., Ajani, J.A., Gu, J., Gong, Y., Qin, A., Hung, M., Wu, X. & Izzo, J.G. 2012. Association of Aurora-A (STK15) kinase polymorphisms with clinical outcome of esophageal cancer treated with preoperative chemoradiation. Cancer 118: 4346-4353.

Qin, J., He, X.F., Wei, W., Liu, Z.Z., Xie, J.J., Wang, W., Du, Y.P., Chen, Y. & Si, H.Q. 2015. Association between the STK15 polymorphisms and risk of cancer: A meta-analysis. Molecular Genetics and Genomics 1: 97-114.

Sakakura, C., Hagiwara, A., Yasuoka, R., Fujita, Y., Nakanishi, M., Masuda, K., Shimomura, K., Nakamura, Y., Inazawa, J., Abe, T. & Yamagishi, H. 2001. Tumour-amplified BTAK is amplified and overexpressed in gastric cancer with possible involvement in aneuploid formation. British Journal of Cancer 84: 824-831.

Tang, W.F., Qiu, H., Ding, H., Sun, B., Wang, L.X., Yin, J. & Gu, H.Y. 2013. Association between the STK15 F31I polymorphism and cancer susceptibility: A meta-analysis involving 43,626 subjects. PLoS ONE 8: e82790.

Xu, L., Zhou, X., Jiang, F., Xu, L. & Yin, R. 2014. STK15 rs2273535 polymorphism and cancer risk: A meta-analysis of 74,896 subjects. Cancer Epidemiology 38: 111-117.

 

 

*Pengarang untuk surat-menyurat; email: leepc@ums.edu.my

 

 

 

 

 

sebelumnya