據以往研究指出飲用水中之過量砷暴露會引起各種疾病，如烏腳病、皮膚癌及膀胱癌等。另有研究指出，全台計有五十萬以上居民的飲水含砷過量大於0.05ppm；因此飲水中砷暴露的健康效應是目前的重要課題。尤其在南台灣的烏腳病流行區，膀胱癌的發生率及死亡率相當高。然而，關於長期飲水中砷暴露所造成的膀胱癌之作用機轉，目前仍未釐清。根據文獻指出，砷暴露會造成有絲分裂期的異常而導致細胞凋亡、中心體異整倍體(centrosome aneuploidy)產生；而異倍體是癌細胞中常見的現象，而此現象與Aurora A(STK15)激酶調控有相關。在眾多癌症研究中更發現有Aurora A過度表現情形；其中主要調控的基因多型性為Aurora-A/STK15 Phe31Ile。抑癌基因p53 Pro72Arg在這個機轉內扮演重要的協助清除與中止異常染色體分裂的作用；但在癌症中時常發現p53變異基因型的不活化作用現象。
因此，本篇研究目的主要是探討台灣西南地區砷暴露與STK15 Phe31Il及p53 Pro72Arg基因多型性與膀胱癌的相關性。
本研究採取以醫院為主體的病例對照研究法：在台灣南部教學醫院選取59個膀胱癌患者為病例組，以及201個家醫科無癌症的就診患者為對照組。所有參與者都經由問卷收集人口學資料、抽菸習慣、飲水史、以及其他相關危險因子。並利用聚合酵素連鎖反應-限制酵素片段長度多型性分析STK15 Phe31Ile及p53 Pro72Arg基因型。
本研究結果：膀胱癌59位，男性46位、女性13位(性比3.5：1)；無癌症對照組201位，男性110位、女性91位(性比1.2：1)。在人口學變項分析發現：男性、學歷較低者、具有抽菸的經歷，膀胱癌危險性較高；並且達統計上顯著差異。危險因子變項分析方面看到：飲用地下水超過15年、飲用地下水於西南沿海高砷暴露區，其膀胱癌危險性顯著高於對照組族群。基因多型性分析發現：STK15 Phe31Ile (T>A)其變異型(AA)與具有變異股(A)其膀胱癌危險性較高OR=2.1 (95% CI=0.8-5.5), p=0.39與OR= 1.8 (95% CI=0.7-4.4), p=0.17；在膀胱癌病人中變異型(AA)較對照組具有高分布頻率50.8%與39.3%。p53 Pro72Arg (C>G)其中間型(GC)其膀胱癌危險性較高OR=1.4 (95% CI=0.7-2.7), p=0.54。STK15基因型具有變異股A數量增加，在無砷暴露時其膀胱癌的危險性上升；反之在高砷暴露時其膀胱癌的危險性修飾下降。p53基因型具有變異股C數量增加，在無砷暴露時其膀胱癌的危險性修飾下降；反之在高砷暴露時其膀胱癌的危險性上升。隨著飲用地下水之累積砷暴露量增加，在不同基因型中都可以發現其膀胱癌的危險性也跟著上升。在兩個基因型都帶有變異股的情況下，其膀胱癌危險性較高OR=1.1 (95% CI=0.3 - 4.7)；尤其在高砷暴露區可以發現基因扮演修飾膀胱癌危險性的作用，達統計上顯著差異OR=4.5 (95% CI=2.1- 9.6), p<0.001。性別、STK15基因多型性、飲用地下水區域、飲用地下水超過15年，多變項迴歸中為膀胱癌危險性的重要因子！
STK15在cell cycle control G2/M中扮演一個相當重要的checkpoint的角色，在本研究中有發現STK15具有變異股A數量增加，其膀胱癌的危險性也跟著上升。當地下水之累積砷暴露量增加，在STK15與p53基因型中都可以發現其膀胱癌的危險性較高。

Objective:
We hereby propose a study to evaluate whether arsenic exposure and functional STK15 (Aurora A) Phe31Ile and p53 Pro72Arg polymorphisms are associated with the risk of bladder cancer in southwestern Taiwan.
Design:
We conducted a hospital-based case-control study and recruit participants through teaching hospitals in southern Taiwan with bladder cancer patients as cases and non-cancer patients as controls. All the participants were interviewed using a standard questionnaire to collect data on demographic characteristics, smoking habits, drinking water history, and other relevant risk factors. The genotypes were determined using polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP).
Result:
We collected 59 bladder cancer patients (46 men and 13 women) as cases and 201 non-cancer patients (with 110 men and 91 women) as controls. Among demographic characteristics, we found that the male gender, lower educational level, and smoking were associated with a higher risk of bladder cancers. In addition, we found that drinking well over fifteen years and in southwestern Taiwan with high arsenic concentration were more frequent in bladder cancer group than in the non-cancer group. In gene polymorphism analysis, we found that both STK15 Phe31Ile (T>A) mutant type (AA) and mutant allele (A) associated with a higher risk of bladder cancers OR=2.1 (95% CI=0.8-5.5, p=0.39) and OR= 1.7 (95% CI=0.7-4.4, p=0.17). Furthermore, mutant type (AA) was more frequent in bladder cancer patients than in non-cancer controls 50.8% vs. 39.3%. p53 Pro72Arg (C>G) with one mutant allele (GC) was associated with a high risk of bladder cancers OR=1.4 (95% CI=0.7-2.7, p=0.54). An increase in mutant allele (A) of STK15 Phe31Ile (T>A) was associated with higher risk of bladder cancers in non-arsenic exposure area, but an increase in mutant allele (A) of STK15 Phe31Ile (T>A) was associated with a lower risk of bladder cancers in high-arsenic exposure area. An increase in mutant allele (C) of p53 Pro72Arg (C>G) was associated with a lower risk of bladder cancers in non-arsenic exposure area, but an increase in mutant allele (C) of p53 Pro72Arg (C>G) was associated with a higher risk of bladder cancers in high-arsenic exposure area. Regardless of geno-types, an increase in arsenic concentration was associated with a higher risk of bladder cancers. When both STK15 Phe31Ile and p53 Pro72Arg carried mutant alleles, we would find a higher risk in bladder cancers OR=1.1 (95% CI=0.3-4.7). Gene polymorphisms act as a modifier of bladder cancers in high CAE concentration group, OR=4.5 (95% CI=2.1-9.6, p<0.001).
Conclusion:
STK15 play an important role in G2/M of cell cycle control: STK15 Phe31Ile (T>A) with mutant type (AA) and mutant allele (A) were related to higher risk of bladder cancers. When both STK15 Phe31Ile and p53 Pro72Arg carried mutant alleles, we would find a higher risk in bladder cancers.

Ahsan H, Chen Y, Kibriya MG, et al. 2003a. Susceptibility to arsenic-induced hyperkeratosis and oxidative stress genes myeloperoxidase and catalase. Cancer Lett 201:57-65.
Ahsan H, Chen Y, Wang Q, Slavkovich V, Graziano JH, et al. 2003b. RM. DNA repair gene XPD and susceptibility to arsenic-induced hyperkeratosis. Toxicol Lett 143:123-31.
Angeloni D, Danilkovitch-Miagkova A, Ivanov SV, Breathnach R, Johnson BE, et al. 2000. Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples. Genes Chromosomes Cancer 29:147-156.
Bischoff JR, Anderson L, Zhu, Y., Mossie, K., Ng, L., Souza, B., et al. 1998. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17: 3052–3065.
Bhattacharyya R, Chatterjee D, Nath B, Jana J, Jacks G, Vahter M, 2003. High arsenic groundwater: mobilization, metabolism and mitigation--an overview in the Bengal Delta Plain. Mol Cell Biochem 253:347-55.
Benbrahim-Tallaa L, Webber MM, Waalkes MP, 2005. Acquisition of androgen independence by human prostate epithelial cells during arsenic-induced malignant transformation. Environ Health Perspect 113:1134-1139.
Carpentier C, Laigle-Donadey F, Marie Y, Auger N, Benouaich-Amiel A, et al. 2006. Polymorphism in Sp1 recognition site of the EGF receptor gene promoter and risk of glioblastoma. Neurology 67:872-784.
Chao TH, Li YH, Chen JH, Wu HL, Guo HR, et al. 2004. The 161TT genotype in the exon 6 of the peroxisome-proliferator-activated receptor gamma gene is associated with premature acute myocardial infarction and increased lipid peroxidation in habitual heavy smokers. Clin Sci 107:461-466.
Chen CJ, Chuang YC, Lin TM, Wu HY. 1985. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res 45:5895-5899.
Chen IJ, Chen CW, Guo HR, Lin MS, Hsiue TR. 2003. The value of carcinoembryonic antigen differentiating malignant from benign pleural effusion. Thoracic Medicine 18:110-115,
Chen HH, Lee BF, Guo HR, Su WR, Chiu NT. 2002a. Changes in bone mineral density of lumbar spine after pelvic radiation therapy. Radiother Oncol 62:239-242.
Chen HH, Su WC, Guo HR, Chang TW, Lee WY. 2002b. p53 and c-erbB-2 but not bcl-2 are predictive of metastasis-free survival in breast cancer receiving post-mastectomy adjuvant radiotherapy in Taiwan. Jpn J Clin Oncol 32:332-339.
Chen HH, Su WC, Guo HR, Lee BF, Su WR, Wu PS, Chiu N-T. 2003. Clinical significance of one to two rib lesions on bone scans in patients of breast cancer without metastases. Nucl Med Commun 24:1167-1174.
Chen PC, Liu MF, Guo HR, Liang CC, Wang CR. 2005. Position 247 of the β2-glycoprotein I gene polymorphism in Chinese patients with antiphospholipid syndrome. APLAR Journal of Rheumatology 8:188–192.
Chen YC, Xu L, Guo YL, et al. 2003. Genetic polymorphism in p53 codon 72 and skin cancer in southwestern Taiwan. Journal of Environmental Science & Health Part A-Toxic/Hazardous Substances & Environmental Engineering 38:201-11.
Cox DG, Hankinson SE, Hunter DJ. 2006. Polymorphisms of the AURKA (STK15/Aurora kinase) gene and breast cancer risk (United States). Cancer Causes Control 17:81-83.
Dasika, G.K.; Lin, S.C.; Zhao, S.; Sung, P.; Tomkinson, A.; Lee, E.Y. 1999. DNA Damage-Induced Cell Cycle Checkpoints and DNA Strand Break Repair in Development and Tumorigenesis. Oncogene 18 (55), 7883-7899.
Ewart-Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, et al. 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.
Germolec DR, Spalding J, Yu HS, Chen GS, Simeonova PP, Humble MC, Bruccoleri A, Boorman GA, Foley JF, Yoshida T, Luster MI. 1998, Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors. Am J Pathol 153:1775-1785.
Guo HR. 2002a. An approach to evaluating occupational and environmental regulatory standards: With a drinking water standard of arsenic as an example. J Occup Health 44:355-359.
Guo HR. 2002b. Cancer risk assessment for arsenic exposure through oyster consumption. Environ Health Perspect 110:123-124.
Guo HR. 2003. The lack of a specific association between arsenic in drinking water and hepatocellular carcinoma. J Hepatol 39:383-388.
Guo HR. 2004. Arsenic level in drinking water and mortality of lung cancer. Cancer Cause and Control. 15:171-177.
Guo HR, Chen CJ, Greene HL. 1994. Arsenic in drinking water and cancers: A descriptive review of Taiwan studies. Environ Geochem Health s16:129-138.
Guo HR, Lipsitz SR, Hu H, Monson RR. 1998. Using ecological data to estimate a regression model for individual data: the association between arsenic in drinking water and incidence of skin cancer. Environ Res 79:82-93.
Guo HR, Yu HS, Hu H, Monson RR. 2001. Arsenic in drinking water and skin cancer: cell-type specificity. Cancer Cause and Control 12:909-916.
Guo HR, Wang NS, Hu H, Monson RR. 2004. Cell-type specificity of lung cancer associated with arsenic ingestion. Cancer Epidemiol Biomarkers Prev 13:638-643.
Ho SY, Guo HR, Chen HH, Pen CJ. 2003. Influence of nutritional status on the survival of terminal cancer patients. J Formos Med Assoc 102:544-550.
Ho SY, Tsai CC, Tsai YC, Guo HR. 2004a. Hepatic angiosarcoma presenting as hepatic rupture in a patient with long-term ingestion of arsenic. J Formos Med Assoc 105:374-379.
Ho SY, Wang YJ, Chen HL, Chen HWH, Wang PM, Guo HR. 2004b. The -308 tumor necrosis factor-脉 promoter gene polymorphism and hepatocellular carcinoma. Cancer Causes and Control 15:657-663.
Ho SY, Guo HR, Jin YT, Tsai ST. 2004c. Prognostic implications of Fas-ligand expression in nasopharyngeal carcinoma. Head Neck 26:977-983.
Ho SY, Tsai YC, Lee MC, Guo HR. 2005. Merkel cell carcinoma in patients with long-term ingestion of arsenic. J Occup Health 47:188-192.
Hsiao WC, Young KC, Lin SL, Lin PW. 2004. Estrogen receptor-alpha polymorphism in a Taiwanese clinical breast cancer population: a case-control study. Breast Cancer Res 6:R180-6.Hutchinson J. Arsenic cancer. 1887. Br Med J 2:1280-1281.
Hwang SL, Guo HR, Hsieh WA, Hwang JS, Lee SD, et al. 2006. Increased cancer risks in a population with prolonged low dose-rate γ-radiation exposure in radiocontaminated buildings, 1983 – 2002. Int J Radiat Biol. 82: 849-858.
Jackson R, Grainge JW. 1975. Arsenic and cancer. Can Med Assoc J 113:396-401.
Hyoungseok J, Hyunmi C, Kim YS, Kim WH, Chunhwa I, et al. 2006. Functional polymorphism 57Val>Ile of aurora kinase A associated with increased risk of gastric cancer progression. Cancer Lett242:273-279.
Kaltreider RC, Davis AM, Lariviere JP, Hamilton JW. 2001. Arsenic alters the function of the glucocorticoid receptor as a transcription factor. Environ Health Perspect 109:245–251.
Kimura MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H. 2005. Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk. Cancer Res 65:3548-3554.
Kuraoka K, Matsumura S, Hamai Y, Nakachi K, Imai K, Matsusaki K, et al. 2003. A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer. Int J Cancer 107:593-596.
Lai HC, Sytwu HK, Sun CA, et al. 2003. Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. Int J Cancer 103:221-5.
Li YH, Chen CH, Yen PS, Lin HJ, Chang BI, Guo HR, et al. 2001. Functional mutation in the promoter region of thrombomodulin gene in relation to carotid artery atherosclerosis. Artherosclerosis 154: 713-719.
Li YH, Chen JH, Tsai WC, Chao TH, Guo HR, et al. 2002. Synergistic effect of thrombomodulin promoter—33G/A polymorphism and smoking on the onset of acute myocardial infarction. Thromb Haemost 87:86-91.
Li YH, Chen JH, Guo HR, Tsai WC, Chao TH. 2002. Genetic risk factors associated with the prognosis of myocardial infarction in young patients. Thromb Haemost 88:694-697.
Lo MC, Hsen YC, Lin KK. 1977. Second Report on the Investigation of Arsenic Content in Underground Water in Taiwan. Taichung, Taiwan: Taiwan Provincial Institute of Environmental Sanitation.
Lo YL, Yu JC, Chen ST, Yang HC, Fann CS, et al. 2005. Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene Aurora-A / STK15 / BTAK. Int J Cancer 115:276-283.
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 Res 64:2680-83.
Marnell LL, Garcia-Vargas GG, Chowdhury UK, et al. 2003. Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem Res Toxicol 16:1507-1513.
Milton AH, Smith W, Rahman B, et al. 2005. Chronic arsenic exposure and adverse pregnancy outcomes in Bangladesh. Epidemiology 16:82-86.
Milam MR, Gu J , Yang H, Celestino J, Wu W, et al. 2007 STK15 F31I polymorphism is associated with increased uterine cancer risk A pilot study. Gynecol Oncol 107:71-74.
Mao JH, Wu D, Jesus PL, Jiang T, Li Q, et al. 2007. Crosstalk between Aurora-A and p53 Frequent Deletion or Downregulation of Aurora-A in Tumors from p53 Null Mice. Cancer Cell 11:161-173.
NIOSH 1975. Criteria Document: Inorganic Arsenic DHEW Pub. NIOSH 75-149.
Paige AJW, Taylor KJ, Taylor C, Hillier SG, Farrington S, Scott D, et al. 2001. WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proceedings of the National Academy of Science, U. S. A. 98:11417-11422.
Pinto D, Vasconcelos A, Costa S, Pereira D, Rodrigues H, Lopes C, Medeiros R. 2004. HER2 polymorphism and breast cancer risk in Portugal. Eur J Cancer Prev 13:177-81.
Simeonova PP, Wang S, Toriuma W, Kommineni V, Matheson J, Unimye N, Kayama F, Harki D, Ding M, Vallyathan V, Luster MI. 2000. Arsenic Mediates Cell Proliferation and Gene Expression in the Bladder Epithelium: Association With Activating Protein-1 Transactivation. Cancer Res 60 (13), 3445-3453.
Sun T, Miao X, Wang J, Tan W, Zhou Y, Yu C, Lin D. 2004. Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma. Carcinogenesis 25:2225-2230.
Tan L-B, Chen K-T, Guo H-R. 2008a. Clinical and epidemiologic features of patients with genitourinary tract tumor in blackfoot disease endemic area of Taiwan. BJU Int 102:48-54.
Tchounwou PB, Wilson B, Isaque A. 1999. Important considerations in the development of public health advisories for arsenic and arsenic-containing compounds in drinking water. Rev Environ Health 14:211-29.
Tseng WP, Chu HM, How S. Wfong JM, Lin CS, Yeh, S. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 40:453-463.
Tseng YS, Tzeng CC, Huang CY, Chen PH, Chiu AW, et al. 2006. Aurora-A overexpression associates with Ha-ras codon-12 mutation and blackfoot disease endemic area in bladder cancer. Cancer Lett 241:93-101.
Trouba KJ, Wauson EM, Vorce RL. 2000. Sodium Arsenite-Induced Dysregulation of Proteins Involved in Proliferative Signaling. Toxicol Appl Pharmacol 164 (2):161-170.
USEPA 1980. Ambient Water Quality Criteria Doc: Arsenic EPA 440/5-84-033.
Vahter M. 2000. Genetic polymorphism in the biotransformation of inorganic arsenic and its role n toxicity. Toxicology Letters 112-113: 209-217.
Vahter M. 2004. Species difference in the metabolism of arsenic compounds. Appl Organomet Chem 8: 175-182.
Vahter M. 1999b. Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog 82: 69-88.
Waalkes MP, Ward JM, Diwan BA. 2004. Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis 25:133-41.
Walton FS, Harmon AW, Paul DS, Drobna Z, Patel YM, Styblo M. 2004. Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes. Toxicol Appl Pharmacol 198:424-33.
Wang L, Habuchi T, Takahashi T, Kamoto T, Zuo T, Mitsumori K, et al. 2002. No association between HER-2 gene polymorphism at codon 655 and a risk of bladder cancer. Int J Cancer 97:787-790.
Wang SL, Chiou JM, Chen CJ, et al. 2003. Prevalence of non-insulin-dependent diabetes mellitus and related vascular diseases in southwestern arseniasis-endemic and nonendemic areas in Taiwan. Environ Health Perspect 111:155-59.
Wang CR, Guo HR, Liu, MF. 2005. RANTE promoter polymorphism in Chinese patients with rheumatoid arthritis. Clin Exp Rheumatol 23:379-784.
Wang YW, Leung WH, Lu PL, Guo HR. 2003. Pre-operative low dose radiotherapy of rectal cancer with Founier’s gangrene: A case report and review of literature. Therapeutic Radiology and Oncology 10:181-187.
World Health Organization. 1987. Environmental Health Critertia: Arsenic.
Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT. 2003. Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans. Environ Health Perspect 111:1421-7.
Zhang W. Stoehlmacher J. Park DJ. Yang D. Borchard E. Gil J. Tsao-Wei DD. Yun J. 2005. Gene polymorphisms of epidermal growth factor receptor and its downstream effectors, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer. Clin Colorectal Canc 5:124-131.
郭浩然：環境與職業流行病學。郭育良等：職業病概論（第二版），pp. 47-84。台北：華杏出版社，2002