• 1.瀘州醫(yī)學院附屬醫(yī)院普外科（四川瀘州 646000）;;
  • 2.四川大學華西醫(yī)院肝膽胰外科（四川成都 610041）;

目的總結膽管癌相關基因甲基化譜的研究進展，闡述DNA甲基化研究對膽管癌的臨床診斷價值和治療意義。方法分析近年來有關膽管癌相關基因異常甲基化與膽管癌關系的文獻報道。結果膽管癌的發(fā)病是多基因異常表達的結果，目前已發(fā)現(xiàn)許多腫瘤相關基因甲基化異常與膽管癌的發(fā)生密切相關。表基因的改變可能是膽管癌發(fā)生過程中非常重要的機理。結論 膽管癌相關基因甲基化異常與膽管癌的發(fā)生關系密切，膽管癌相關基因異常甲基化檢測有望為膽管癌的早期無創(chuàng)診斷提供新的途徑。改變DNA甲基轉移酶活性和膽管癌相關基因甲基化狀況可作為膽管癌輔助治療的一種新思路。

引用本文： 薛立新,李可洲. 膽管癌相關基因甲基化研究進展. 中國普外基礎與臨床雜志, 2011, 18(6): 672-675. doi: 復制

1. Harder J, Blum HE.. Cholangiocarcinoma [J]. Praxis (Bern 1994), 2002, 91(34): 13521356.
2. Maruyama R, Toyooka S, Toyooka KO, et al. Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features [J]. Clin Cancer Res, 2002, 8(2): 514519.
3. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer [J]. Nat Rev Genet, 2002, 3(6): 415428.
4. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer [J]. Nat Genet, 2003, 33 Suppl: 238244.
5. Singal R, Ginder GD. DNA methylation [J]. Blood, 1999, 93(12): 40594070.
6. Yang B, House MG, Guo M, et al. Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma [J]. Mod Pathol, 2005, 18(3): 412420.
7. Lee S, Kim WH, Jung HY, et al. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma [J]. Am J Pathol, 2002, 161(3): 10151022.
8. Tozawa T, Tamura G, Honda T, et al. Promoter hypermethylation of DAPkinase is associated with poor survival in primary biliary tract carcinoma patients [J]. Cancer Sci, 2004, 95(9): 736740.
9. Isomoto H. Epigenetic alterations associated with cholangiocarcinoma (review) [J]. Oncol Rep, 2009, 22(2): 227232.
10. Klump B, Hsieh CJ, Dette S, et al. Promoter methylation of INK4a/ARF as detected in bilesignificance for the differential diagnosis in biliary disease [J]. Clin Cancer Res, 2003, 9(5): 17731778.
11. Koga Y, Kitajima Y, Miyoshi A, et al. Tumor progression through epigenetic gene silencing of O(6)methylguanineDNA methyltransferase in human biliary tract cancers [J]. Ann Surg Oncol, 2005, 12(5): 354363.
12. Hong SM, Choi J, Ryu K, et al. Promoter hypermethylation of the p16 gene and loss of its protein expression is correlated with tumor progression in extrahepatic bile duct carcinomas [J]. Arch Pathol Lab Med, 2006, 130(1): 3338.
13. Chinnasri P, Pairojkul C, Jearanaikoon P, et al. Preferentially different mechanisms of inactivation of 9p21 gene cluster in liver flukerelated cholangiocarcinoma [J]. Hum Pathol, 2009, 40(6): 817826.
14. Kim BH, Cho NY, Shin SH, et al. CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma [J]. Virchows Arch, 2009, 455(4): 343351.
15. Wong N, Li L, Tsang K, et al. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma [J]. J Hepatol, 2002, 37(5): 633639.
16. Liu XF, Zhu SG, Zhang H, et al. The methylation status of the TMS1/ASC gene in cholangiocarcinoma and its clinical significance [J]. Hepatobiliary Pancreat Dis Int, 2006, 5(3): 449453.
17. Tischoff I, Markwarth A, Witzigmann H, et al. Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors [J]. Int J Cancer, 2005, 115(5): 684689.
18. Abraham SC, Lee JH, Boitnott JK, et al. Microsatellite instability in intraductal papillary neoplasms of the biliary tract [J]. Mod Pathol, 2002, 15(12): 13091317.
19. Limpaiboon T, Khaenam P, Chinnasri P, et al.Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma [J]. Cancer Lett, 2005, 217(2): 213219.
20. Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL6/STAT3 signaling in cholangiocarcinoma cells due to SOCS3 epigenetic silencing [J]. Gastroenterology, 2007, 132(1): 384396.
21. McGinnis W, Krumlauf R. Homeobox genes and axial patterning [J]. Cell, 1992, 68(2): 283302.
22. Roberts DJ, Smith DM, Goff DJ, et al. Epithelialmesenchymal signaling during the regionalization of the chick gut [J]. Development, 1998, 125(15): 2791801.
23. Uchida T, Wada K, Akamatsu T, et al. A novel epidermal growth factorlike molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB4 in MKN28 gastric cancer cells [J]. Biochem Biophys Res Commun, 1999, 266(2): 593602.
24. Young J, Biden KG, Simms LA, et al. HPP1: a transmembrane proteinencoding gene commonly methylated in colorectal polyps and cancers [J]. Proc Natl Acad Sci USA, 2001, 98(1): 265270.
25. McCormick MB, Tamimi RM, Snider L, et al. NeuroD2 and neuroD3: distinct expression patterns and transcriptional activation potentials within the neuroD gene family [J]. Mol Cell Biol, 1996, 16(10): 57925800.
26. Ogino S, Cantor M, Kawasaki T, et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies [J]. Gut, 2006, 55(7): 10001006.
27. Kim BH, Cho NY, Choi M, et al. Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas [J]. Arch Pathol Lab Med, 2007, 131(6): 923930.
28. Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and Kras mutations in intrahepatic cholangiocarcinoma of the liver [J]. Gut, 2000, 47(5): 721727.
29. Chen YJ, Tang QB, Zou SQ. Inactivation of RASSF1A, the tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma [J]. World J Gastroenterol, 2005, 11(9): 13331338.
30. Hermann A, Gowher H, Jeltsch A. Biochemistry and biology of mammalian DNA methyltransferases[J]. Cell Mol Life Sci, 2004, 61(1920): 25712587.
31. Fang JY, Yang L, Zhu HY, et al. 5Aza2’deoxycitydine induces demethylation and upregulates transcription of p16INK4A gene in human gastric cancer cell lines [J]. Chin Med J (Engl), 2004, 117(1): 99103.
32. 唐啟彬, 孫華文, 鄒聲泉. 5氮2脫氧胞苷體內外抑制膽管癌細胞生長的研究 [J]. 中華普通外科雜志, 2004, 19(5): 295297.
  1. 1. Harder J, Blum HE.. Cholangiocarcinoma [J]. Praxis (Bern 1994), 2002, 91(34): 13521356.
  2. 2. Maruyama R, Toyooka S, Toyooka KO, et al. Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features [J]. Clin Cancer Res, 2002, 8(2): 514519.
  3. 3. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer [J]. Nat Rev Genet, 2002, 3(6): 415428.
  4. 4. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer [J]. Nat Genet, 2003, 33 Suppl: 238244.
  5. 5. Singal R, Ginder GD. DNA methylation [J]. Blood, 1999, 93(12): 40594070.
  6. 6. Yang B, House MG, Guo M, et al. Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma [J]. Mod Pathol, 2005, 18(3): 412420.
  7. 7. Lee S, Kim WH, Jung HY, et al. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma [J]. Am J Pathol, 2002, 161(3): 10151022.
  8. 8. Tozawa T, Tamura G, Honda T, et al. Promoter hypermethylation of DAPkinase is associated with poor survival in primary biliary tract carcinoma patients [J]. Cancer Sci, 2004, 95(9): 736740.
  9. 9. Isomoto H. Epigenetic alterations associated with cholangiocarcinoma (review) [J]. Oncol Rep, 2009, 22(2): 227232.
  10. 10. Klump B, Hsieh CJ, Dette S, et al. Promoter methylation of INK4a/ARF as detected in bilesignificance for the differential diagnosis in biliary disease [J]. Clin Cancer Res, 2003, 9(5): 17731778.
  11. 11. Koga Y, Kitajima Y, Miyoshi A, et al. Tumor progression through epigenetic gene silencing of O(6)methylguanineDNA methyltransferase in human biliary tract cancers [J]. Ann Surg Oncol, 2005, 12(5): 354363.
  12. 12. Hong SM, Choi J, Ryu K, et al. Promoter hypermethylation of the p16 gene and loss of its protein expression is correlated with tumor progression in extrahepatic bile duct carcinomas [J]. Arch Pathol Lab Med, 2006, 130(1): 3338.
  13. 13. Chinnasri P, Pairojkul C, Jearanaikoon P, et al. Preferentially different mechanisms of inactivation of 9p21 gene cluster in liver flukerelated cholangiocarcinoma [J]. Hum Pathol, 2009, 40(6): 817826.
  14. 14. Kim BH, Cho NY, Shin SH, et al. CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma [J]. Virchows Arch, 2009, 455(4): 343351.
  15. 15. Wong N, Li L, Tsang K, et al. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma [J]. J Hepatol, 2002, 37(5): 633639.
  16. 16. Liu XF, Zhu SG, Zhang H, et al. The methylation status of the TMS1/ASC gene in cholangiocarcinoma and its clinical significance [J]. Hepatobiliary Pancreat Dis Int, 2006, 5(3): 449453.
  17. 17. Tischoff I, Markwarth A, Witzigmann H, et al. Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors [J]. Int J Cancer, 2005, 115(5): 684689.
  18. 18. Abraham SC, Lee JH, Boitnott JK, et al. Microsatellite instability in intraductal papillary neoplasms of the biliary tract [J]. Mod Pathol, 2002, 15(12): 13091317.
  19. 19. Limpaiboon T, Khaenam P, Chinnasri P, et al.Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma [J]. Cancer Lett, 2005, 217(2): 213219.
  20. 20. Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL6/STAT3 signaling in cholangiocarcinoma cells due to SOCS3 epigenetic silencing [J]. Gastroenterology, 2007, 132(1): 384396.
  21. 21. McGinnis W, Krumlauf R. Homeobox genes and axial patterning [J]. Cell, 1992, 68(2): 283302.
  22. 22. Roberts DJ, Smith DM, Goff DJ, et al. Epithelialmesenchymal signaling during the regionalization of the chick gut [J]. Development, 1998, 125(15): 2791801.
  23. 23. Uchida T, Wada K, Akamatsu T, et al. A novel epidermal growth factorlike molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB4 in MKN28 gastric cancer cells [J]. Biochem Biophys Res Commun, 1999, 266(2): 593602.
  24. 24. Young J, Biden KG, Simms LA, et al. HPP1: a transmembrane proteinencoding gene commonly methylated in colorectal polyps and cancers [J]. Proc Natl Acad Sci USA, 2001, 98(1): 265270.
  25. 25. McCormick MB, Tamimi RM, Snider L, et al. NeuroD2 and neuroD3: distinct expression patterns and transcriptional activation potentials within the neuroD gene family [J]. Mol Cell Biol, 1996, 16(10): 57925800.
  26. 26. Ogino S, Cantor M, Kawasaki T, et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies [J]. Gut, 2006, 55(7): 10001006.
  27. 27. Kim BH, Cho NY, Choi M, et al. Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas [J]. Arch Pathol Lab Med, 2007, 131(6): 923930.
  28. 28. Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and Kras mutations in intrahepatic cholangiocarcinoma of the liver [J]. Gut, 2000, 47(5): 721727.
  29. 29. Chen YJ, Tang QB, Zou SQ. Inactivation of RASSF1A, the tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma [J]. World J Gastroenterol, 2005, 11(9): 13331338.
  30. 30. Hermann A, Gowher H, Jeltsch A. Biochemistry and biology of mammalian DNA methyltransferases[J]. Cell Mol Life Sci, 2004, 61(1920): 25712587.
  31. 31. Fang JY, Yang L, Zhu HY, et al. 5Aza2’deoxycitydine induces demethylation and upregulates transcription of p16INK4A gene in human gastric cancer cell lines [J]. Chin Med J (Engl), 2004, 117(1): 99103.
  32. 32. 唐啟彬, 孫華文, 鄒聲泉. 5氮2脫氧胞苷體內外抑制膽管癌細胞生長的研究 [J]. 中華普通外科雜志, 2004, 19(5): 295297.