血漿硒濃度、尿中砷濃度及硒蛋白基因多形性與攝護腺癌

Plasma Selenium Concentration, Urine Arsenic Concentration, Polymorphism of Selenoprotein and Prostate Cancer

蔡承軒(Cheng-Shiuan Tsai)

指導教授 ： 薛玉梅

臺北醫學大學/公共衛生暨營養學院/公共衛生學系暨研究所/碩士(2014年)

摘要

摘要
背景
攝護腺癌是源自攝護腺的惡性腫瘤，過去攝護腺癌主要被認為是西方男性常見的癌症，臨床上常以攝護腺特異性抗原作為第一線監測指標，並與腫瘤嚴重程度有關。然而近年來，在亞洲如新加坡、韓國與日本等國家攝護腺癌發生率也不斷的攀升。過去研究指出，環境砷暴露會增加攝護腺癌標準化死亡率，但至今仍未知砷暴露的內在劑量生物標記與攝護腺癌的關係。此外，硒被認為可以延緩攝護腺癌疾病進程的微量元素，硒蛋白-P (selenoprotein P, SEPP1)基因多形性可能修飾硒的功能。在實驗性與觀察性研究中均發現硒與砷之間可能存在交互作用。因此，本研究欲探討血漿硒濃度、尿液總砷濃度及硒蛋白基因多形性與攝護腺癌之相關性，並闡明其是否有交互作用。
方法
本研究為年齡(?b5歲)匹配之病例對照研究，於2005年6月至2013年8月間，臺大醫院、臺北市立萬芳醫院與臺北醫學大學附設醫院泌尿科門診與病房招募295位攝護腺癌病例，及295名健康檢查民眾。向研究對象說明目的並獲得同意書後，進行問卷訪視並收集血液與尿液樣本。血液用以萃取DNA並利用聚合酶鏈鎖反應-限制片段長度多形性(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, PCR-RFLP)進行硒蛋白基因多形性分析。血漿經消化後，以感應耦合電漿質譜儀(Inductively Coupled Plasma Mass. Spectrometry; ICP-MS)測定硒濃度。尿液無機砷、單甲基砷酸、雙甲基砷酸等砷物種濃度以高效能液相層析儀連接氫化器及原子吸收光譜儀(High Performance Liquid Chromatography-linked Hydride Generator and Atomic Absorption Spectrometry, HPLC-HG-AAS)分析。
結果
高教育程度、父親或母親氏族為外省籍或原住民比閩南人有較低的攝護腺癌危險對比值。血漿硒濃度較高攝護腺癌危險對比值顯著較低，且呈顯著負向劑量效應關係。SEPP1 rs3797310合併CT與TT基因型相較於CC基因型者，對於攝護腺癌危險對比值具有邊緣顯著保護作用，但調整教育程度與父母親氏族後，未達顯著水準。病例組的尿液總砷濃度雖較對照組略高，但無差異。進一步分析血漿硒濃度與尿中總砷濃度後，在病例組中發現尿中總砷濃度與血漿硒濃度呈顯著正相關。低血漿硒濃度且高尿液總砷濃度者比起高血漿硒濃度且低尿液總砷濃度者增加攝護腺癌危險對比值，呈劑量效應關係。在臨床病理資料部分觀察到攝護腺特異性抗原與尿中總砷濃度呈顯著正相關，高攝護腺特異性抗原濃度較低攝護腺特異性抗原濃度者有較高的攝護腺癌的期別與級別，高血漿硒濃度較低血漿硒濃度者有較低的攝護腺癌的期別與級別，而高尿液總砷濃度者較低尿液總砷濃度者有較高的攝護腺癌的期別與級別。且低血漿硒濃度同時具有高攝護腺特異性抗原濃度者比起高血漿硒濃度同時具有低攝護腺特異性抗原濃度者有較高的攝護腺癌的期別與級別，高尿液總砷濃度同時具有高攝護腺特異性抗原濃度者比起低尿液總砷濃度同時具有低攝護腺特異性抗原濃度者有較高的攝護腺癌期別與級別，低血漿硒濃度同時具有高尿液總砷濃度者比起高血漿硒濃度同時具有低尿液總砷濃度者有較高的攝護腺癌期別與級別。
結論
教育程度較高與父母親氏族為原住民會降低攝護腺癌之危險對比值，本研究結果顯示血漿硒濃度較高與攝護腺癌危險對比值顯著降低相關，也有較低的腫瘤期別和級別。尿液砷濃度越高，有較高的攝護腺癌腫瘤期別和級別，攝護腺特異性抗原越高，有較高的攝護腺癌腫瘤期別和級別。此外，隨血漿硒濃度降低和尿液砷濃度增加其攝護腺癌的危險對比值顯著增加;同時攝護腺癌也有較高的腫瘤期別和級別；隨攝護腺特異性抗原增加和血漿硒濃度降低，攝護腺癌有較高的腫瘤期別和級別；而隨攝護腺特異性抗原增加和尿液砷濃度增加，攝護腺癌有較高的腫瘤期別和級別。
關鍵字
攝護腺癌、血漿硒濃度、尿中砷濃度、攝護腺特異性抗原、期別、級別、疾病嚴重度、交互作用

關鍵字

攝護腺癌 ； 血漿硒濃度 ； 尿中砷濃度 ； 攝護腺特異性抗原 ； 期別 ； 級別 ； 疾病嚴重度 ； 交互作用

並列摘要

Abstract
Background
Prostate Cancer (PC) is a malignant tumor originated in prostate and is a second common male’s cancer in the world, and the most common cancer in men in Europe, North America, and some parts of Africa. However, incidence of PC in Singapore, China, Korea and Japan, those Asia countries, have still been rising over the past few decades. Prostate specific antigen (PSA) is a kind of glandular kallikrein related peptidase released from prostate, and PSA level can predict both risk and severity of PC, therefore, PSA level testing has being used to screen PC. As an antioxidant, selenium can slow down prostate cancer tumor progression, but the association between plasma selenium levels and risk of aggressive prostate cancer may be modified by different genotype of selenoprotein.
Many studies reported those significant dose-response relationships between arsenic concentration in drinking-water and the mortality of prostate cancer in Taiwan. Both experimental and observational studies revealed a possible association between selenium and arsenic. The aim of this study is to determine the relationship between plasma selenium, polymorphism of selenoprotein, urinaty total arsenic, and prostate cancer.

Methods
Two hundred ninety five pathologically-confirmed cases of PC and 295 cancer-free controls were individually matched to case subjects by age (?b 5 years) were recruited from Department of Urology of National Taiwan University Hospital, Taipei Municipal Wan Fang Hospital and Taipei Medical University Hospital. Personal interview and biospeciment of urine and blood collection from participants were conducted by well-trained interviewers after participants’ informed consent was obtained. Plasma selenium was measured by an inductively coupled plasma mass. Urinary arsenic concentration was detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of SEPP1rs3797310 and SEP15 rs5859 were determined using polymerase chain reaction-restriction fragment length polymorphism method. The odds ratio and 95% confidence interval of risk factors on prostate cancer was analyzed by unconditional logistic regression. The joint effects of plasma selenium and urinary total arsenic on the OR of PC were estimated by the synergy index.

Results
Subjects who had higher educational levels had a lower OR of PC than those with lower educational levels. Mainland Chinese or Aboriginal had a significantly lower OR of PC than the Fukien Taiwanese. The higher plasma selenium was the lower OR of PC with a dose-response relationship. Prostate cancer patients with high plasma selenium had low tumor stage and grade. Participants carried SEPP1rs3797310 CT+TT genotype compared to those with CC genotype had a lower OR of PC in crude model; then this relationship was disappeared after confounder was adjusted. Urinary arsenic concentration was not different between prostate cancer patients and controls. Prostate cancer patients with high urinary total arsenic concentration had high tumor stage and grade. Urinary total arsenic concentration was significantly positively related with plasma selenium and PSA concentration. Participants with lower plasma selenium concentration and higher urinary total arsenic concentration compared to those with higher plasma selenium concentration and lower urinary total arsenic concentration had a higher OR of PC with a dose-response relationship. On the other hand, prostate cancer patients with low plasma selenium and high urinary total arsenic, or those with low plasma selenium and high PSA level or those with high urinary total arsenic and high PSA level had a high tumor stage and high grade.

Conclusion
Educational level and parents’ ethnic was related to the OR of PC. High plasma selenium was significantly associated with a low OR of PC and a low stage and grade status of PC. Prostate cancer patients with high urinary total arsenic or high PSA concentration had high tumor stage and tumor grade. Low plasma selenium interacted with high urinary total arsenic on high tumor stage and tumor grade. Participants with lower plasma selenium concentration and higher urinary total arsenic concentration compared to those with higher plasma selenium concentration and lower urinary total arsenic concentration had a higher OR of PC.

Keywords
Prostate cancer, Plasma selenium concentration, Urinary arsenic concentration, Prostate Specific Antigen, Stage, Grade, Severity of disease, Interaction

並列關鍵字

Prostate cancer ； Plasma selenium concentration ； Urinary arsenic concentration ； Prostate Specific Antigen ； Stage ； Grade ； Severity of disease ； Interaction

參考文獻

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