NA修復基因MGMT啟動子區過甲基化在膽管癌中的作用_《中國普外基礎與臨床雜志》

作者：

劉小方 , 孫憲春 , 張翠生 , 許政 , 李紹軍 , 周先亭 , 孫世杰

青島大學醫學院附屬煙臺毓璜頂醫院肝膽外科(山東煙臺 264000);

關鍵詞：

膽管癌 6-氧-甲基鳥嘌呤-DNA甲基轉移酶甲基化特異性聚合酶鏈反應表遺傳性過甲基化

視頻：

導出 下載 收藏 掃碼 引用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

目的探討膽管癌組織中6-氧-甲基鳥嘌呤-DNA甲基轉移酶(MGMT)基因的甲基化狀態及其在膽管癌中的臨床意義。方法采用甲基化特異性PCR(MSP)和免疫組織化學法分析膽管癌組織中MGMT基因啟動子甲基化狀態及MGMT蛋白表達情況，并分析MGMT基因甲基化狀態與臨床病理特征的關系。結果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15例，陰性表達21例，21例MGMT蛋白陰性表達的膽管癌中MGMT甲基化陽性14例; 15例MGMT蛋白陽性表達中MGMT甲基化陽性僅3例。MGMT蛋白表達與MGMT甲基化狀態呈負相關(rs=-0.816, P lt;0.05)。MGMT基因的甲基化狀態與膽管癌患者的腫瘤浸潤深度、分化程度及TNM分期有關(P lt;0.05)，但與患者的年齡、性別、病理學類型、淋巴結轉移均無關(P gt;0.05)。結論MGMT基因啟動子過甲基化是膽管癌組織中常見的分子事件，并可能與膽管癌發生有關，MGMT甲基化狀態可以作為評價膽管癌惡性程度的一項指標。

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修復基因MGMT啟動子區過甲基化在膽管癌中的作用. 中國普外基礎與臨床雜志, 2011, 18(9): 947-951. doi: 復制

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狀與展望 [J]．中國普外基礎與臨床雜志， 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，梁力建．肝門部膽管癌外科治療的若干問題 [J]．中國普外基礎與臨床雜志， 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治療 [J]．中國普外基礎與臨床雜志， 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. 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狀與展望 [J]．中國普外基礎與臨床雜志， 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，梁力建．肝門部膽管癌外科治療的若干問題 [J]．中國普外基礎與臨床雜志， 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治療 [J]．中國普外基礎與臨床雜志， 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.

《中國普外基礎與臨床雜志》

NA修復基因MGMT啟動子區過甲基化在膽管癌中的作用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

《中國普外基礎與臨床雜志》

NA修復基因MGMT啟動子區過甲基化在膽管癌中的作用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

摘要全文圖表視頻參考文獻施引文獻補充材料