Promoter Hypermethylation of DNA Repair Gene MGMT in Cholangiocarcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Xiaofang , SUN Xianchun , ZHANG Cuisheng , XU Zheng , LI Shaojun , ZHOU Xianting , SUN Shijie

Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University Medical College, Yantai 264000, Shandong Province, China;

Corresponding author：

Keywords：

Cholangiocarcinoma; O6-methylguanine-DNA methyltransferase gene; Methylation specific PCR; Epigenetic; Hypermethylation

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ObjectiveTo explore the clinical significance of promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) in cholangiocarcinoma. MethodsPromoter methylation status of MGMT gene and expression of MGMT protein were detected in cholangiocarcinoma by methylationspecific PCR and immunohistochemical staining, respectively. ResultsAberrant methylation of MGMT gene was detected in 17 patients (47.2%). Twentyone cases showed negative immunoreactivities. Of 21 patients with negative MGMT expression, 14 patients had aberrant methylation of MGMT gene. In 15 patients with positive MGMT expression, aberrant methylation of MGMT gene was only found in three cases. There was a negative correlation between promoter methylation status of MGMT gene and the expression of MGMT protein (rs=-0.816, P lt;0.05). Promoter methylation status of MGMT gene was related to depth of invasion, degree of differentiation, and TNM stage (P lt;0.05), but not to age of patient, gender, pathological type, and lymph node metastasis (P gt;0.05). ConclusionsHypermethylation of MGMT promoter is a frequency molecular event in cholangiocarcinoma and may be involved in carcinogenesis. Methylation status of MGMT gene may be used to evaluate malignant degree of cholangiocarcinoma.

Citation： LIU Xiaofang,SUN Xianchun,ZHANG Cuisheng,XU Zheng,LI Shaojun,ZHOU Xianting,SUN Shijie,.. Promoter Hypermethylation of DNA Repair Gene MGMT in Cholangiocarcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(9): 947-951. doi: Copy

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.	邹声泉．胆管癌外科治疗的现状与展望 [J]．中国普外基础与临床杂志， 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.	何强，梁力建．肝门部胆管癌外科治疗的若干问题 [J]．中国普外基础与临床杂志， 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.
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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.	胡超华，胡若男，熊杰，等．肝门部胆管癌的手术治疗 [J]．中国普外基础与临床杂志， 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. 邹声泉．胆管癌外科治疗的现状与展望 [J]．中国普外基础与临床杂志， 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. 何强，梁力建．肝门部胆管癌外科治疗的若干问题 [J]．中国普外基础与临床杂志， 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. 胡超华，胡若男，熊杰，等．肝门部胆管癌的手术治疗 [J]．中国普外基础与临床杂志， 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Promoter Hypermethylation of DNA Repair Gene MGMT in Cholangiocarcinoma

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