台灣代謝酵素基因多形性與乳癌相關性之研究

目的：當乳房上皮細胞受到活性氧的破壞時會造成細胞趨向癌化，因此本實驗欲探討不同代謝酵素基因多形性與乳癌發生率的相關性。材料與方法：本實驗共收集 260位女性乳癌病人及224位正常人之5ml 的EDTA血液分析代謝酵素基因基因多形性。分析的項目如下：①去除環境致癌物的代謝酵素：細胞色素P450 2E1(cytochrome P450 2E1，CYP2E1)及榖胱苷肽轉移酶M1(glutathione s-transferase M1，GSTM1)之基因多型性;②氧化性傷害相關酵素: 含錳超氧自由基歧化酵素 (Manganese superoxide dismutase，MnSOD)及榖胱甘肽過氧化酶（glutathione peroxidase 1，GPx1）、骨髓過氧化酶 (myeloperoxidase，MPO)、過氧化氫酶（catalase，CAT）【CAT -15A>T 、 CAT -262C>T】之基因多型性。結果: ①基因多形性與乳癌的關係：以具CYP2E1 -1053C>T CC基因型者為基準，具CYP2E1 -1053C>T TT基因型之婦女，其罹患乳癌的機率較低。(OR=0.26，p<0.05)。具MnSOD 1183T>C帶有C攜帶者及GPx1Pro198Leu帶有T攜帶者的乳癌病患，無論是在allele frequency、genotype frequency或phenotype frequency，其罹患乳癌的機率較低(MnSOD : OR=0.41、0.57、0.58，p<0.005；GPx1 : OR=0.17、0.15、0.19，p<0.001)。至於具有 MPO -463G>A基因型者、CAT -15A>T基因型者、CAT -262C>T基因型者及 GSTM1基因型者均未達到統計學上之顯著意義。②以同時具有CYP2E1 -1053C>T CC基因型者與MnSOD 1183T>C TT基因型者為基準，具CYP2E1-1053C>T CC基因型者與MnSOD 1183T>C帶有C攜帶者之組合群及CYP2E1 -1053C>T帶有T攜帶者與MnSOD 1183T>C帶有C攜帶者之組合群，其罹患乳癌的機率較低(OR=0.60、0.46，p<0.05)；以同時具有CYP2E1-1053C>T CC基因型者與GPx1 Pro198Leu CC基因型者為基準，具CYP2E1-1053C>T CC基因型與GPx1 Pro198Leu帶有T攜帶者之組合群及CYP2E1-1053C>T帶有T攜帶者與GPx1 Pro198Leu帶有T攜帶者之組合群，其罹患乳癌的機率較低(OR=0.12、0.18，p<0.001) ③以同時具有MnSOD 1183T>C TT及GSTM1表現型為基準，MnSOD 1183T>C帶有C攜帶者及GSTM1不表現型之組合群，其罹患乳癌的機率較低(OR=0.54，p<0.05)；以同時具有MnSOD 1183T>C TT基因型及CAT -15A>T AA 基因型為基準，MnSOD 1183T>C帶有C攜帶者及CAT -15A>T (AA基因型或帶有T攜帶者)之組合群，其罹患乳癌的機率較低(OR=0.56、0.55，p<0.05)；以同時具有MnSOD 1183T>C TT基因型及CAT -262C>T CC基因型為基準，MnSOD 1183T>C帶有C攜帶者及CAT -262C>T CC基因型之組合群，其罹患乳癌的機率較低(OR=0.56，p<0.001)；以同時具有MnSOD 1183T>C TT基因型及MPO -463G>A GG基因型為基準，MnSOD 1183T>C帶有C攜帶者及MPO -463G>A (GG基因型或帶有A攜帶者)之組合群，其罹患乳癌的機率較低(OR=0.49、0.43，p<0.001)。④以同時具有MnSOD 1183T>C TT基因型及GPx1 Pro198Leu CC基因型為基準，MnSOD 1183T>C (TT基因型或帶有C攜帶者)之組合群與GPx1 Pro198Leu帶有T攜帶者，其罹患乳癌的機率較低(OR=0.22、0.07，p<0.001)。結論：由本實驗結果可見，若具有氧化性傷害相關酵素MnSOD 1183C攜帶者、GPx1T攜帶者或去除致癌物的代謝酵素CYP2E1 -1053T基因者，可能與降低乳癌的發生率有關。

關鍵字

代謝性酵素；基因多形性

並列摘要

Objectives: Damage to breast epithelium by reactive oxygen species is important in the initiation and promotion of cells to neoplastic growth. Therefore, this study investigated the genomic polymorphisms of metabolic enzymes, including detoxification and oxidative stress-related enzymes, associated with the risk of breast cancer. Materials and Methods: 5ml of EDTA blood was taken from 260 patients admitted to breast cancer surgery from Kaohsiung Medical University Hospital and 224 controls. Genomic polymorphisms of detoxification enzymes, including CYP2E1, GSTM1, and oxidative stress related-enzymes, including manganese superoxide dismutase (MnSOD) , glutathione peroxidase1 (GPx1), myeloperoxidase (MPO）, and catalase 【CAT -15A>T, and CAT -262C>T】were analyzed. Results: ①Compared with the subjects with the CYP2E1 -1053C>T CC genotype, those with the CYP2E1 -1053C>T TT genotype have a decreased risk of breast cancer (OR=0.26, p<0.05). In addition, those with the MnSOD 1183T>C C carrier rather than those with the MnSOD 1183T>C wild-type were predisposed to having a decreased risk of breast cancer, regardless of their allele, genotype (CC) and phenotype frequencies.（OR=0.41, 0.57 and 0.58 respectively, p<0.005） Furthermore, those with the GPx1 Pro198Leu T carrier rather than those with the GPx1 Pro198Leu wild-type were predisposed to having a decreased risk of breast cancer, regardless of their allele, genotype (CT) and phenotype frequencies. (OR=0.17, 0.15 and 0.19 respectively, p<0.001).② Those with the combimed genotypes for the CYP2E1 -1053C>T CC and MnSOD 1183T>C C carrier, and the combimed genotypes for the CYP2E1 -1053C>T T carrier and MnSOD 1183T>C C carrier rather than those with the CYP2E1 -1053C>T CC and MnSOD 1183T>C TT genotypes were predisposed to having a decreased risk of breast cancer (OR=0.60 and 0.46 respectively, p<0.05 ); those with the combimed genotypes for the CYP2E1 -1053C>T CC and GPx1 Pro198Leu T carrier, and the combimed genotypes for the CYP2E1 -1053C>T T carrier and GPx1Pro198Leu T carrier rather than those with the CYP2E1 -1053C>T CC and GPx1Pro198Leu CC genotypes were predisposed to having a decreased risk of breast cancer (OR=0.12 and 0.18 respectively, p<0.001 ). ③ Those with the combimed genotypes for the MnSOD 1183T>C C carrier and GSTM1 null-type rather than those with the MnSOD 1183T>C TT and GSTM1 wild-type genotypes were predisposed to having a decreased risk of breast cancer (OR=0.54, p<0.05); those with the combimed genotypes for the MnSOD 1183T>C C carrier and CAT -15A>T AA, and the combimed genotypes for the MnSOD 1183T>C C carrier and CAT -15A>T T carrier rather than those with the MnSOD 1183T>C TT and CAT -15A>T AA genotypes were predisposed to having a decreased risk of breast cancer (OR=0.56 and 0.55 respectively, p<0.05); those with the combimed genotypes for the MnSOD 1183T>C C carrier and CAT -262C>T CC rather than those with the MnSOD 1183T>C TT and CAT -262C>T CC genotypes were predisposed to having a decreased risk of breast cancer (OR=0.56, p<0.001); those with the combimed genotypes for the MnSOD 1183T>C C carrier and MPO -463G>A GG and the combimed genotypes for the MnSOD 1183T>C C carrier and MPO -463G>A A carrier genotypes rather than those with the MnSOD 1183 T>C TT and MPO -463G>A GG genotypes were predisposed to having a decreased risk of breast cancer (OR=0.49 and 0.43 respectively, p<0.001). ④ Those with the the combimed genotypes for the MnSOD 1183T>C TT and GPx1Pro198Leu T carrier and the combimed genotypes for the MnSOD 1183T>C C carrier and GPx1 Pro198Leu T carrier genotypes rather than those with the MnSOD 1183T>C TT and GPx1Pro198Leu CC genotypes were predisposed to having a decreased risk of breast cancer. (OR=0.22 and 0.07 respectively, p<0.001) Conclusion: We suggested that the subjects with the CYP2E1-1053 T carrier、MnSOD 1183 C carrier, GPx1 T carrier have a decreased risk for breast cancer.