• 青島大學(xué)醫(yī)學(xué)院附屬煙臺(tái)毓璜頂醫(yī)院肝膽外科(山東煙臺(tái) 264000);

目的探討膽管癌組織中6-氧-甲基鳥嘌呤-DNA甲基轉(zhuǎn)移酶(MGMT)基因的甲基化狀態(tài)及其在膽管癌中的臨床意義。方法采用甲基化特異性PCR(MSP)和免疫組織化學(xué)法分析膽管癌組織中MGMT基因啟動(dòng)子甲基化狀態(tài)及MGMT蛋白表達(dá)情況，并分析MGMT基因甲基化狀態(tài)與臨床病理特征的關(guān)系。結(jié)果36例膽管癌組織中MGMT基因17例(47.2%)為甲基化陽性; MGMT蛋白陽性表達(dá)15例，陰性表達(dá)21例，21例MGMT蛋白陰性表達(dá)的膽管癌中MGMT甲基化陽性14例; 15例MGMT蛋白陽性表達(dá)中MGMT甲基化陽性僅3例。MGMT蛋白表達(dá)與MGMT甲基化狀態(tài)呈負(fù)相關(guān)(rs=-0.816, P lt;0.05)。MGMT基因的甲基化狀態(tài)與膽管癌患者的腫瘤浸潤(rùn)深度、分化程度及TNM分期有關(guān)(P lt;0.05)，但與患者的年齡、性別、病理學(xué)類型、淋巴結(jié)轉(zhuǎn)移均無關(guān)(P gt;0.05)。結(jié)論MGMT基因啟動(dòng)子過甲基化是膽管癌組織中常見的分子事件，并可能與膽管癌發(fā)生有關(guān)，MGMT甲基化狀態(tài)可以作為評(píng)價(jià)膽管癌惡性程度的一項(xiàng)指標(biāo)。

引用本文： 劉小方,孫憲春,張翠生,許政,李紹軍,周先亭,孫世杰. NA修復(fù)基因MGMT啟動(dòng)子區(qū)過甲基化在膽管癌中的作用. 中國(guó)普外基礎(chǔ)與臨床雜志, 2011, 18(9): 947-951. doi: 復(fù)制

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1. Guza R, Ma L, Fang Q, et al. Cytosine methylation effects on the repair of O6methylguanines within CG dinucleotides [J]. J Biol Chem, 2009, 284(34): 2260122610.
2. Guza R, Rajesh M, Fang Q, et al. Kinetics of O6methyl2′deoxyguanosine repair by O6alkylguanine DNA alkyltransferase within Kras genederived DNA sequences [J]. Chem Res Toxicol, 2006, 19(4): 531538.
3. Sobin LH, Wittekind C. TNM classification of malignant tumors: international union against cancer [M]. 5th ed. New York: Wiley, 1997: 5962.
4. Mosconi S, Beretta GD, Labianca R, et al. Cholangiocarcinoma [J]. Crit Rev Oncol Hematol, 2009, 69(6): 259270.
5. Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma [J]. Lancet, 2005, 366(8): 13031314.
6. 鄒聲泉． 膽管癌外科治療的現(xiàn)狀與展望 [J]． 中國(guó)普外基礎(chǔ)與臨床雜志， 2008， 15(2)： 7780．.
7. Shaib Y, Elserag HB. The epidemiology of cholangiocarcinoma [J]. Semin Liver Dis, 2004, 24(2): 115125.
8. 何強(qiáng)， 梁力建． 肝門部膽管癌外科治療的若干問題 [J]． 中國(guó)普外基礎(chǔ)與臨床雜志， 2009， 16(11)： 869872．.
9. Paik WH, Park YS, Hwang JH, et al. Palliative treatment with selfexpandable metallic stents in patients with advanced type Ⅲ or Ⅳ hilar cholangiocarcinoma: a percutaneous versus endoscopic approach [J]. Gastrointest Endosc, 2009, 69(1): 5562.
10. Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 19902009 [J]. World J Gastroenterol, 2009, 15(34): 42404262.
11. Welzel TM, Graubard BI, Elserag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a populationbased casecontrol study [J]. Clin Gastroenterol Hepatol, 2007, 5(10): 12211228.
12. 胡超華， 胡若男， 熊杰， 等． 肝門部膽管癌的手術(shù)治療 [J]．中國(guó)普外基礎(chǔ)與臨床雜志， 2009， 16(11)： 873874．.
13. Fontijn D, Adema AD, Bhakat KK, et al. O6methylguanineDNAmethyltransferase promoter demethylation is involved in basic fibroblast growth factor induced resistance against temozolomide in human melanoma cells [J]. Mol Cancer Ther, 2007, 6(10): 28072815.
14. Gerson SL. Clinical relevance of MGMT in the treatment of cancer [J]. J Clin Oncol, 2002, 20(9): 23882399.
15. Alvino E, Castiglia D, Caporali S, et al. A single cycle of treatment with temozolomide, alone or combined with O6benzylguanine,induces strong chemoresistance in melanoma cell clones in vitro: role of O6methylguanineDNA methyltransferase and the mismatch repair system [J]. Int J Oncol, 2006, 29(4): 785797.
16. Watanabe T, Katayama Y, Komine C, et al. O6methylguanineDNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course [J]. Int J Cancer, 2005, 113(4): 581587.
17. Bello MJ, Alonso ME, Amioso C, et al. Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors [J]. Mutat Res, 2004, 554(12): 2332.
18. Whitehall VL, Walsh MD, Young J, et al. Methylation of O6methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with lowlevel DNA microsatellite instability [J]. Cancer Res, 2001, 61(3): 827830.
19. Shen L, Kondo Y, Rosner GL, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer [J]. J Natl Cancer Inst, 2005, 97(18): 13301338.
20. Nakamura M, Watanabe T, Yonekawa Y, et al. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene [J]. Carcinogenesis, 2001, 22(10): 17151719.
21. Myong NH. Role of loss of o6methylguanine DNA methyltransferase (MGMT) expression in NonSmall Cell Lung Carcinomas (NSCLCs): with reference to the relationship with p53 overexpression [J]. Cancer Res Treat, 2010, 42(2): 95100.
22. Kohya N, Miyazaki K, Matsukura S, et al. Deficient expression of O6methylguanineDNA methyltransferase combined with mismatchrepair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma [J]. Ann Surg Oncol, 2002, 9(4): 371379.
23. SI BE, Lee HS, Kim SH, et al. Inactivation of O6methylguanineDNA methyltransferase by promoter CpG island hypermethylation in gastric cancers [J]. Br J Cancer, 2002, 86(12): 18881892.
24. Koga Y, Kitajima Y, Miyoshi A, et al. Tumor progression through epigenetic gene silencing of O6methylguanineDNA methyltransferase in human biliary tract cancers [J]. Ann Surg Oncol, 2005, 12(5): 354363.
25. Soejima H, Zhao W, Mukai T. Epigenetic silencing of the MGMT gene in cancer [J]. Biochem Cell Biol, 2005, 83(4): 429437.
26. Munot K, Bell SM, Lane S, et al. Pattern of expression of genes linked to epigenetic silencing in human breast cancer [J]. Hum Pathol, 2006, 37(8): 989999.
  1. 1. Guza R, Ma L, Fang Q, et al. Cytosine methylation effects on the repair of O6methylguanines within CG dinucleotides [J]. J Biol Chem, 2009, 284(34): 2260122610.
  2. 2. Guza R, Rajesh M, Fang Q, et al. Kinetics of O6methyl2′deoxyguanosine repair by O6alkylguanine DNA alkyltransferase within Kras genederived DNA sequences [J]. Chem Res Toxicol, 2006, 19(4): 531538.
  3. 3. Sobin LH, Wittekind C. TNM classification of malignant tumors: international union against cancer [M]. 5th ed. New York: Wiley, 1997: 5962.
  4. 4. Mosconi S, Beretta GD, Labianca R, et al. Cholangiocarcinoma [J]. Crit Rev Oncol Hematol, 2009, 69(6): 259270.
  5. 5. Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma [J]. Lancet, 2005, 366(8): 13031314.
  6. 6. 鄒聲泉． 膽管癌外科治療的現(xiàn)狀與展望 [J]． 中國(guó)普外基礎(chǔ)與臨床雜志， 2008， 15(2)： 7780．.
  7. 7. Shaib Y, Elserag HB. The epidemiology of cholangiocarcinoma [J]. Semin Liver Dis, 2004, 24(2): 115125.
  8. 8. 何強(qiáng)， 梁力建． 肝門部膽管癌外科治療的若干問題 [J]． 中國(guó)普外基礎(chǔ)與臨床雜志， 2009， 16(11)： 869872．.
  9. 9. Paik WH, Park YS, Hwang JH, et al. Palliative treatment with selfexpandable metallic stents in patients with advanced type Ⅲ or Ⅳ hilar cholangiocarcinoma: a percutaneous versus endoscopic approach [J]. Gastrointest Endosc, 2009, 69(1): 5562.
  10. 10. Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 19902009 [J]. World J Gastroenterol, 2009, 15(34): 42404262.
  11. 11. Welzel TM, Graubard BI, Elserag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a populationbased casecontrol study [J]. Clin Gastroenterol Hepatol, 2007, 5(10): 12211228.
  12. 12. 胡超華， 胡若男， 熊杰， 等． 肝門部膽管癌的手術(shù)治療 [J]．中國(guó)普外基礎(chǔ)與臨床雜志， 2009， 16(11)： 873874．.
  13. 13. Fontijn D, Adema AD, Bhakat KK, et al. O6methylguanineDNAmethyltransferase promoter demethylation is involved in basic fibroblast growth factor induced resistance against temozolomide in human melanoma cells [J]. Mol Cancer Ther, 2007, 6(10): 28072815.
  14. 14. Gerson SL. Clinical relevance of MGMT in the treatment of cancer [J]. J Clin Oncol, 2002, 20(9): 23882399.
  15. 15. Alvino E, Castiglia D, Caporali S, et al. A single cycle of treatment with temozolomide, alone or combined with O6benzylguanine,induces strong chemoresistance in melanoma cell clones in vitro: role of O6methylguanineDNA methyltransferase and the mismatch repair system [J]. Int J Oncol, 2006, 29(4): 785797.
  16. 16. Watanabe T, Katayama Y, Komine C, et al. O6methylguanineDNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course [J]. Int J Cancer, 2005, 113(4): 581587.
  17. 17. Bello MJ, Alonso ME, Amioso C, et al. Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors [J]. Mutat Res, 2004, 554(12): 2332.
  18. 18. Whitehall VL, Walsh MD, Young J, et al. Methylation of O6methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with lowlevel DNA microsatellite instability [J]. Cancer Res, 2001, 61(3): 827830.
  19. 19. Shen L, Kondo Y, Rosner GL, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer [J]. J Natl Cancer Inst, 2005, 97(18): 13301338.
  20. 20. Nakamura M, Watanabe T, Yonekawa Y, et al. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene [J]. Carcinogenesis, 2001, 22(10): 17151719.
  21. 21. Myong NH. Role of loss of o6methylguanine DNA methyltransferase (MGMT) expression in NonSmall Cell Lung Carcinomas (NSCLCs): with reference to the relationship with p53 overexpression [J]. Cancer Res Treat, 2010, 42(2): 95100.
  22. 22. Kohya N, Miyazaki K, Matsukura S, et al. Deficient expression of O6methylguanineDNA methyltransferase combined with mismatchrepair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma [J]. Ann Surg Oncol, 2002, 9(4): 371379.
  23. 23. SI BE, Lee HS, Kim SH, et al. Inactivation of O6methylguanineDNA methyltransferase by promoter CpG island hypermethylation in gastric cancers [J]. Br J Cancer, 2002, 86(12): 18881892.
  24. 24. Koga Y, Kitajima Y, Miyoshi A, et al. Tumor progression through epigenetic gene silencing of O6methylguanineDNA methyltransferase in human biliary tract cancers [J]. Ann Surg Oncol, 2005, 12(5): 354363.
  25. 25. Soejima H, Zhao W, Mukai T. Epigenetic silencing of the MGMT gene in cancer [J]. Biochem Cell Biol, 2005, 83(4): 429437.
  26. 26. Munot K, Bell SM, Lane S, et al. Pattern of expression of genes linked to epigenetic silencing in human breast cancer [J]. Hum Pathol, 2006, 37(8): 989999.