CA9基因多型性對台灣泌尿上皮癌易感性及臨床病理表徵之影響

Impacts of CA9 Gene Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathologic Characteristics in Taiwan

王賢祥(Shian-Shiang Wang)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2014年)

https://doi.org/10.6834/CSMU.2014.00102

摘要

泌尿上皮細胞覆蓋在腎盞到膀胱的管腔內襯中，在此泌尿通道中最常見的惡性腫瘤便是泌尿上皮細胞癌。在台灣，膀胱癌的發生率在男性是第九位，女性則是第十六位；腎盂及輸尿管癌的發生率在男性是第十五位，女性是第十三位。在這些部位的癌症中，不論男女，泌尿上皮細胞癌皆佔了百分之九十以上。碳酸酐酶包含一個族群的鋅金屬酶，能有效催化二氧化碳與碳酸氫根間的可逆反應。第九型碳酸酐酶能幫助腫瘤細胞，在缺氧微環境下維持適合腫瘤細胞增殖的酸鹼度。在大多數正常組織中，第九型碳酸酐酶並不存在，但在很多癌細胞中卻會過度表現，也因此常被視為腫瘤指標。單核苷酸多型性是指在一特定族群中至少百分之一以上發生去氧核糖核酸中單一核苷酸的變異。過去文獻報告指出，第九型碳酸酐酶的單核苷酸多型性和轉移性腎細胞癌的整體存活有關，也可能改變口腔癌的易感性及轉移。本研究在探討第九型碳酸酐酶基因多型性與泌尿上皮細胞癌易感性、臨床病理表現間之關聯。
共有442 位研究對象參與本研究，包括221位健康對照組與221位泌尿上皮細胞癌患者。個人資料是以問卷方式取得，內容包括年齡、性別、抽菸史。臨床資料則自病歷中獲得，包括腫瘤臨床分期、淋巴轉移及癌細胞分級。至於DNA檢體則以聚合酶連鎖反應(Polymerase chain reaction， PCR)、即時定量聚合酶連鎖反應（Real-time polymerase chain reaction， Real-time PCR）來分析CA9基因的4個單核苷酸多型性；包括+201(rs2071676)、+1081(rs3829078)、+1584(rs1048638)及376del393。
在調整其他共變數後發現，個體若在CA9 rs1048638攜帶至少一個A對偶基因者比原型基因CC型者有2.203倍風險得到泌尿上皮細胞癌，而且有較高侵犯性腫瘤的機會。若加上抽菸，泌尿上皮細胞癌患者在CA9 rs1048638帶有至少一個A對偶基因者，有高達4.75倍機會得到侵犯性腫瘤。CA9 rs1048638基因多型性可作為預測泌尿上皮細胞癌的易感性及病理表徵的指標。本研究結果提供證據顯示，CA9基因變異是台灣泌尿上皮細胞癌腫瘤生成的危險因子

關鍵字

第九型碳酸酐酶；基因多型性；單核苷酸多型性；泌尿上皮細胞癌

並列摘要

Urothelium covers the epithelial lining of the urinary tract from the renal calyces to the bladder. The most frequent malignant tumor of urinary tract is urothelial cell carcinoma (UCC). In Taiwan, bladder cancer is the ninth leading malignancy among men and the sixteenth leading malignancy among women. Renal pelvis and ureter cancer is the fifteen leading cancer among men and the thirteen leading cancer among women. UCC composed more than 90% of the cancer in both genders. Carbonic anhydrase (CA), a family of zinc metalloenzymes, can efficiently catalyze the reversible processes of hydration-dehydration of CO2 and HCO3-. CAIX helps to keep a normal pH in tumor cells in a hypoxic microenvironment and allow tumor cell proliferation. CAIX, which is not expressed in most benign tissues, is reportedly over-expressed in several types of carcinomas and generally considered a marker of malignancy. Single nucleotide polymorphism (SNP) is a variation in the DNA sequence that occurs when a nucleotide (A, T, C, or G) is changed in at least 1% of a certain population. Previous study showed that SNP of CA9 is associated with overall survival for metastatic renal cell carcinoma and might alter oral cancer susceptibility and metastasis. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma and the clinicopathological status.
A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Medical information for the cases was obtained from their medical records, and included cigarette smoking history, TNM clinical staging and histological grade. Their genomic DNA samples were subjected to polymerase chain reaction (PCR) and real-time PCR genotyping analysis to analyze the genetic polymorphisms. Allelic discrimination of the CA9 +201(rs2071676), +1081(rs3829078),+1584(rs1048638) and 376del393 allelic polymorphisms were assessed.
After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC) carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05) than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoking, people with at least one A allele of CA9 polymorphisms (rs1048638) had a 4.75-fold (95% Confidence Interval = 1.204–18.746) increased risk of invasive cancer. The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This study provided insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan.

並列關鍵字

carbonic anhydrase 9 (CA9) ； gene polymorphism ； single nucleotide polymorphism ； urothelial cell carcinoma

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