進階搜尋


 
系統識別號 U0026-0812200911254540
論文名稱(中文) 南台灣乳癌之相關基因多型性
論文名稱(英文) Genetic polymorphisms associated with breast cancer in south Taiwan
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 93
學期 1
出版年 94
研究生(中文) 王雪閔
研究生(英文) Shuei-Ming Wang
電子信箱 ubiqutin@yahoo.com.tw
學號 t3691103
學位類別 碩士
語文別 中文
論文頁數 84頁
口試委員 口試委員-楊孔嘉
口試委員-蘇五洲
指導教授-黃溫雅
召集委員-周楠華
中文關鍵字 乳癌  去氧核醣核酸修復  雌激素代謝  基因多型性 
英文關鍵字 genetic polymorphism  DNA repair  Breast cancer  estrogen metabolism 
學科別分類
中文摘要   乳癌 (breast cancer) 是台灣婦女癌症死亡率之首。超過45%的遺傳性乳癌患者是由於乳癌易感基因一/二 (breast cancer susceptibility gene 1/2; BRCA1/2) 發生突變所造成。我們收集189位女性乳癌患者以及421位年齡相仿的健康女性作為對照組,利用限制性片段長度多型性 (restriction fragment length polymorphism; RFLP) 的方法,分析BRCA2與同為去氧核醣核酸修復 (DNA repair) 基因的RAD51之基因多形性 (genetic polymorphism),以探討其與家族性 (familial) 或自發性 (sporadic) 乳癌之相關性。
  此外,參與在雌激素代謝 (estrogen metabolism) 中的基因,在調整個人乳癌之感受性方面亦可能扮演著重要的角色,並且可能為自發性乳癌的危險因子。因此,為了研究基因多型性與自發性乳癌之相關性,我們亦分析對於雌激素代謝相當重要的非自然存在之合成有機物代謝酵素 (xenobiotic metabolism enzyme; XME) 基因的基因多型性。
  在研究過程中,我們發現有許多自發性乳癌病人的家族成員帶有其他種類的癌症。為了確定基因多型性是否能預測家族中其他癌症的發生,家族中有其他癌症發生之乳癌患者其XME基因多型性亦進行分析。
  根據研究結果,我們發現在南台灣BRCA2 N372H及RAD51 g135c基因多型性並未對乳癌風險有明顯之貢獻。而在我們的研究當中也沒有發現猶太人中BRCA1/2的常見突變點 (hotspot mutation),BRCA1 185delAG、BRCA1 5382insC與BRCA2 6174delT。另外,我們亦未發現由Li SL等人於1999年所發表位於BRCA1 intron 7上10個鹼基對的缺失 (deletion)。 XME基因之變異,特別是GST酵素,會影響細胞去毒性的活性。XME基因變異的程度與乳癌及其他癌症的風險有強烈之關聯。XME基因之變異可作為預測家族中其他癌症發生的有用指標。


英文摘要  Breast cancer is the leading cause of cancer mortality among women in Taiwan. More than 45% of inherited breast cancers are caused by mutations in breast cancer susceptibility gene 1/2 (BRCA1/2). In this study, we collected 189 female patients of breast cancer and 421 controls. The single nucleotide polymorphisms in the BRCA2 as well as RAD51 DNA repair genes are examined for their association with familial/sporadic breast cancers by restriction fragment length polymorphism (RFLP) method.
 In addition, genes involved in the estrogen metabolism play potential role in modulating individual susceptibility to breast cancer and appeared as good candidates for risk factors in the etiology of sporadic breast cancer. To investigate the genetic polymorphisms associated with sporadic breast cancer, the SNPs in xenobiotic metabolism enzyme (XME) genes, which are important for estrogen metabolism, are examined in this study, too.
 In our study, we found that a large amount of sporadic breast cancer patients have family members that suffer from other types of cancers. To identify the genetic polymorphisms associated with familial predisposition to cancers, the patients with familial histories of various cancers are examined for their genotypes in various XME genes.
 Results in this study indicate that no significant risk for breast cancer is attributed by BRCA2 N372H and RAD51 g135c in south Taiwan. The BRCA1 185delAG and 5382insC as well as BRCA2 6174delT, the BRCA1/2 hotspot mutations in Ashkenazi Jewishs, were not identified in our subjects. Also, the 10 bp-deletion of BRCA1 intron 7, identified by Li SL et al, was not observed in our study. Mutations in XME genes, especially the GST enzymes, affect the detoxification activities in cells. Levels of variations in XME genes are strongly correlated with breast cancers as well as other types of cancers. Genetic variation in XME genes is a useful marker for familial cancer predisposition.


論文目次 中文摘要……………………………………………………………………..I
英文摘要……………………………………………………………………III
誌謝……………………………………………………………………………IV
目錄…………………………………………………………………………V
表目錄………………………………………………………………………IX
圖目錄及附錄………………………………………………………………X
縮寫表...…………………………………………………………………………XI
1. 緒論………………………………………………………………………1
1.1 乳癌流行病學 (epidermiology)………………………………………1
1.2 雌激素 (estrogen) 的生成與代謝………………………………………3
1.3 非自然有機物代謝酵素 (XMEs )……………………………………5
1.4 核酸雙股斷裂修復路徑 (double strand break repair pathway)……7
1.5 乳癌易感基因 (BRCA gene)………………………………………9
1.6 單一核酸多型性 (SNP)………………………………………………………10
1.7 核酸修復路徑之基因多型性……………………………………………11
1.7.1 Breast cancer susceptibility gene 2 (BRCA2)…………………………11
1.7.2 Radiation-resistant gene 51 (RAD51)…………………………………12
1.8 非自然有機物代謝酵素之基因多型性………………………………………13
1.8.1 Cytochrome P450 1A1 (CYP1A1)…………………………………………13
1.8.2 Catechol-O-methyltransferase (COMT)………………………………………14
1.8.3 N-acetyltransferase gene 2 (NAT2)………………………………………15
1.8.4 Glutathione S-transferase (GST)………………………………………16
1.8.5 Manganese superoxide dismutase (MnSOD)………………………………………17
1.9 研究方向………………………………………………19
2. 材料與方法……………………………………………………21
2.1 研究對象…………………………………………………21
2.2 檢體收集與問卷…………………………………………………22
2.3 全血DNA萃取…………………………………………………………22
2.3.1 紅血球溶解液製備…………………………………………22
2.3.2 酚-氯仿DNA萃取法………………………………………………23
2.4 聚合酶連鎖反應 (PCR)………………………………………………24
2.5 限制性片段長度多型性 (RFLP)…………………………………………25
2.6 Amplification created restriction site (ACRS)………………………26
2.7 凝膠電泳……………………………………………………26
2.8 統計分析…………………………………………………27
3. 結果……………………………………………………29
3.1 家族癌症史分組……………………………………………29
3.2 基因多型性與乳癌…………………………………………29
3.3 基因多型性與家族性乳癌………………………………………31
3.4 基因多型性間相互作用與乳癌…………………………………………33
3.5 GST基因間相互作用與乳癌………………………………………35
3.6 GST危險性基因型個數與自發性乳癌………………………………………36
4. 討論………………………………………38
4.1 基因頻率與過去研究之比較…………………………………………38
4.2 基因多型性與乳癌………………………………………39
4.3 基因多型性與家族性乳癌………………………………………40
4.4 基因多型性間相互作用與乳癌………………………………………41
4.5 GST危險性基因型個數與自發性乳癌………………………………………42
4.6 基因多型性與其他乳癌危險因子………………………………………42
4.7 結論………………………………………………………………43
參考文獻………………………………………45
表格………………………………………54
圖………………………………………65
附錄………………………………………69
自述………………………………………71
參考文獻 行政院衛生署,民國九十三年衛生統計,衛生署,台北,2004。

國衛院癌症研究組,乳癌診斷與治療共識,國家衛生研究院,台北,1998。

張曉卉,妳可以不必怕乳癌,康健雜誌23期,天下,台北,2000。

Ambrosome CB, Freudenheim JL, Graham S, Marshall JR, Vena JE, Brasure JR, Laughlin R, Nemoto T, Michalek AM, Harrington A and et al. Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. Cancer Res. 1995, 55: 3483-5.

Ambrosone CB, Freudenheim JL, Thompson PA, Bowman E, Vena JE, Marshall JR, Graham S, Laughlin R, Nemoto T and Shields PG. Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res. 1999, 59: 602-6.

Bartsch H, Nair U, Risch A, Rojas M, Wikman H and Alexandrov K. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol. Biomarkers Prev. 2000, 9: 3-28.

Blasiak J, Przybylowska K, Czechowska A, Zadrozny M, Pertynski T, Rykala J, Kolacinska A, Morawiec Z and Drzewoski J. Analysis of the G/C poltmorphism in the 5’-untranslated region of the RAD51 gene in breast cancer. Acta Biochimica Polonica 2003, 50: 249-53.

Carter RF. BRCA1, BRCA2 and breast cancer: a concise clinical review. Clin. Invest. Med. 2001, 24: 147-57.

Cavalieri E, Frenkel K, Liehr JG, Rogan E and Roy D. Estrogens as endogenous genotoxic agents DNA adducts and mutations. J. Natl. Cancer Inst. 2000, 27: 75-93.

Charrier J, Maugard CM, Mevel BL and Bignon YJ. Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility. Br. J. Cancer 1999, 79: 346-53.

Cheng TC, Chen ST, Huang CS, Fu YP, Yu JC, Cheng CW, Wu PE and Shen CY. Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. Int. J. Cancer 2005, 113: 345-53.

Doll MA, Fretland AJ, Deitz AC and Hein DW. Determination of human NAT2 acetylator genotype by restriction fragment-length polymorphism and allele-specific amplification. Analytical Biochem. 1995, 231: 413-20.
Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder B and Easton DF. A systematic review of genetic polymorphisms and breast cancer. Cancer Epidemiol. Biomarkers Prev. 1999, 8: 843-54.

Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST and Eng CM. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am. J. Hum. Genet. 1998, 63: 45-51.

Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD and 27 others. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am. J. Hum. Genet. 1998, 62: 676-89.

Fridovich I. Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 1995, 64: 97-112.

Garte S, Gaspari L, Alexandrie AK, Ambrosonw C, Autrup H, Autrup J, Baranova LH and et al. Metabolic gene polymorphism frequencies in normal control populations. Cancer Epidemiol. Biomarkers Prev. 2001, 10: 1239-48.

Gruber CJ, Tschugguel W, Schneebergr C and Huber JC. Production and actions of estrogens. N. Eng. J. Med. 2002, 346: 340-52.

Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B and King MC. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990, 250: 1684-9.

Hartman AR and Ford JM. BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nature Genet. 2002, 32: 180-4.

Healey CS, Dunning AM, Teare MD, Chase D, Parker L, Burn J, Chang-Claude J, Mannermaa A, Kataja V, Huntsman DG, Pharoah P, Luben RN, Easton DF and Ponder B. A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nature Genet. 2000, 26: 362-4.

Helzlsouer KJ, Selmin O, Huang HY, Strickland PT, Hoffman S, Alberg AJ, Easton M, Comstock GW and Bell D. Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J. Natl. cancer Inst. 1998, 90: 512-8.

Hoeijmakers Jan HJ. Genome maintenance mechanisms for preventing cancer. Nature 2001, 411: 366-74.

Hsand F and Henderson BE. Estrogen and breast cancer. Carcinogenesis 1996, 17: 2279-84.

Huang CS, Chem HD, Chang KJ, Cheng CW, Hsu SM and Shen CY. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res. 1999, 59: 4870-5.

Huang CS, Chem HD, Chang KJ, Shen CY, Hsu SM and Chang KJ. Association between N-acetyltransferase (NAT2) genetic polymorphism and development of breast cancer in post-menopausal Chinese women in Taiwan, an area of great increase in breast cancer incidence. Int. J. Cancer 1999, 82: 175-9.

Huang CS, Shen CY, Chang KJ, Hsu SM and Chem HD. Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Br. J. Cancer 1999, 80: 1838-43.

Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C and Kouzarides T. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 2003, 115: 523-35.

Ishiben, Hankinson SE, Colditz GA, Spiegelman D, Willert WC, Speizer FE, Kelsey KT and Hunter DJ. Cigarette smoking, cytochrome P450 1A polymorphisms, and beast cancer risk in the Nurse’ Health Study. Cancer Res. 1998, 58: 667-71.

Ishitobi M, Miyoshi Y, Ando A, Hasegawa S, Egawa C, Tamaki Y, Monden M and Noguchi S. Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis. Clin. Cancer Res. 2003, 9: 1376-80.

Jakubowska A, Narod SA, Goldgar DE, Mierzejewski M, Masojc B, Nej K, Huzarska J, Byrski T, Gorski B and Lubinski J. Breast cancer risk reduction associated with RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland. Cancer Epidemiol. Biomarkers Prev. 2003, 12: 457-9.

Khanna KK and Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 2001, 27: 247-54.

Krajinovic M, Ghadirian P, Richer C, Sinnett H, Gandini S, Perret C, Lacroix A, Labuda D and Sinnett D. Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. Int. J. Cancer 2001, 92: 220-5.

Landeghem GF, Tabatabaie P, Kucinskas V, Saha N and Beckman G. Ethnic variation in the mitochondrial targeting sequence polymorphism of MnSOD. Hum. Hered. 1999, 49: 190-3.

Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P and Gershoni-Baruch R. A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc. Natl. Acad. Sci. USA 2001, 98: 3232-6.

Li JJ, Oberley LW, Clair DK, Ridnour LA and Oberley TD. Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase. Oncogene 1995, 10: 1989-2000.

Li SS, Tseng HM, Yang TP, Liu CH, Teng SJ, Huang HW, Chen LM, Kao HW, Chen JH, Tseng JN, Chen A, Hou MF, Huang TJ, Chang HT, Mok KT and Tsai JH. Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan. Hum. Genet. 1999, 104: 201-4.

Lieber MR, Ma Y, Pannicke U and Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Mol. Cell Biol. 2003, 4: 712-20.

Lin HJ, Han CY, Lin BK and Hardy S. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology. Amer. J. Hum. Genet. 1993, 52: 827-834.

Lo YL, Yu JC, Huang CS, Tseng SL, Chang TM, Chang KJ, Wu CW and Shen CY. Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int. J. Cancer 1998, 79: 580-7.

MacLachlan TK, Takimoto R and El-Deiry WS. BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets. Mol. Cell. Bio. 2002, 22: 4280-92.

Matsui A, Ikeda T, Enomoto K, Nakashima H, Omae K, Watanabe M, Hibi T and Kitajima M. Progression of human breast cancers to metastatic state is linked to genotypes of catechol-O-methyltransferase. Cancer Lett. 2000, 150: 23-31.

Millikan R, Pittman G, Tse CK, Savitz DA, Newman B and Bell D. Glutathione S-transferase M1, T1, and P1 and breast cancer. Cancer Epidemiol. Biomarkers Prev. 2000, 9: 567-73.

Mitrunen K, Sillanpaa P, Kataja V, Eskelinen M, Kosma VM, Benhamou S, Uusitupa M and Hirvonen A. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 2001, 22: 827-9.

Mitrunen K and Hirvonen A. Molecular epidemiology of sporadic breast cancer: The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutation Res. 2003, 544: 9-41.

Mucci LA, Wedren S, Tamimi RM, Trichopoulos D and Adami HO. The role of gene-environment interaction in the etiology of human cancer: examples from cancers of the large bowel, lung and breast. J. Int. Med. 2001, 249: 477-93.
Oberley LW and Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979, 39: 1141-9.

Park SK, Yoo KY, Lee SJ, Kim SU, Ahn SH, Noh DY, Choc KJ, Strickland PT, Hirvonen A and Kang D. Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk. Pharmacogenetics 2000, 10: 301-9.

Piver MS, Baker TR, Jishi MF, Sandecki AM, Tsukada Y, Natarajan N, Mettlin CJ and Blake CA. Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 1993, 71: 582-8.

Ratnasinghe D, Yao S, Tangrea JA, Qiao Y, Andersen MR, Barrett MJ and et al. Polymorphisms of DNA repair gene XRCC1 and lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 2001, 10:119-23.

Rohrdanz F and Kahl R. Alterations of antioxidant enzyme expression in response to hydrogen peroxide. Free Radic. Biol. Med. 1998, 24: 27-38.

Rosenblum JS, Gilula NB and Lerner RA. On signal sequence polymorphisms and diseases of distribution. Proc. Natl. Acad. Sci. U.S.A. 1996, 93: 4471-3.

Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-Hattori Y, Shimizu Y and Mizuno Y. Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson’s disease. Biochem. Biophys. Res. Commun. 1996, 226: 561-5.

Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC and Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New Eng. J. Med. 1997, 336: 1401-8.

Taioli E, Bradlow HL, Garbers SV, Sepkovic DW, Osborne MP, Trachman J, Ganguly S and Garte SJ. Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk. Cancer Detect. Prev., 1999, 23: 232-7.

Thompson PA, Shields PG, Freudenheim JL, Stone A, Vena JE, Marshall JR, Graham S, Laughlin R, Nemoto T, Kadlubar FE and Ambrosome CB. Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk. Cancer Res. 1998, 58: 2107-10.

Thompson PA and Ambrosone CB. Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. J. Natl. Cancer Inst. Monogr. 2000, 27: 125-34.

Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002, 108: 171-82.

Wang WW, Spurdle AB, Kolachana P, Bove B, Modan B, Ebbers SM, Suthers G, Tucker MA, Kaufman DJ, Doody MM, Tarone RE, Daly M, Levavi H, Pierce H, Chetrit A, kConFab, ABCFS/CFRBCS, AJBCS, NISOC, Yechezkel GH, Chenevix-trench G, Offit K, Godwin AK and Struewing JP. A single nucleotide polymorphism in the 5’ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol. Biomarkers Prev. 2001, 10: 955-60.

Williams JA. Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression. Carcinogenesis 2001, 22: 209-14.

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G, Barfoot R, Hamoudi R, Patel S, Rice C, Biggs P, Hashim Y, Smith A, Connor F, Arason A, Gudmundsson J, Ficenec D, Kelsell D, Ford D, Tonin P, Bishop DT, Spurr NK, Ponder B, Eeles R, Peto J, Devilee P, Cornelisse C, Lynch H, Narod S, Lenoir G, Egilsson V, Barkadottir RB, Easton DF, Bentley DR, Futreal PA, Asheorth A and Stratton MR. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995, 378: 789-92.

Xia F, Taghian DG, DeFrank JS, Zeng ZC, Willers H, Iliakis G and Powell SN. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc. Natl. Acad. Sci. U.S.A. 2001, 15: 8644-9.

Yim DS, Park SK, Yoo KY, Yoon KS, Chung HH, Kang HL, Ahn SH, Noh DY, Choe KJ, Jang IJ, Shin SG, Strickland PT, Hirvonen A and Kang D. Relationship between the Val158Met polymorphism of catechol-O- methyltransferase and breast cancer. Pharmacogenetics 2001, 11: 279-86.

Zhu BT and Conney AH. Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? Cancer Res. 1998, 58: 2269-77.

http://herkules.oulu.fi/isbn95142358576/html/x309.html

SNP website, http://ncbi.nlm.nih.gov/SNP/index.htm

uhealthy健康醫療網,http://www.uhealthy.com/chinese/taiwan.htm

沈志陽,尋找乳癌發生的原因,中央研究院生物醫學科學研究所,http://www.ibms.sinica.edu.tw/html/7_4/p1.htm

財團法人長庚紀念醫院全球資訊網,www.cgmh.com.tw/intr/intr1/c12100/ 乳癌資訊網/保健/Breast%20risk.htm
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2005-02-02起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2005-02-02起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw