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

目的總結(jié)膽管癌相關(guān)基因甲基化譜的研究進(jìn)展，闡述DNA甲基化研究對(duì)膽管癌的臨床診斷價(jià)值和治療意義。方法分析近年來(lái)有關(guān)膽管癌相關(guān)基因異常甲基化與膽管癌關(guān)系的文獻(xiàn)報(bào)道。結(jié)果膽管癌的發(fā)病是多基因異常表達(dá)的結(jié)果，目前已發(fā)現(xiàn)許多腫瘤相關(guān)基因甲基化異常與膽管癌的發(fā)生密切相關(guān)。表基因的改變可能是膽管癌發(fā)生過(guò)程中非常重要的機(jī)理。結(jié)論 膽管癌相關(guān)基因甲基化異常與膽管癌的發(fā)生關(guān)系密切，膽管癌相關(guān)基因異常甲基化檢測(cè)有望為膽管癌的早期無(wú)創(chuàng)診斷提供新的途徑。改變DNA甲基轉(zhuǎn)移酶活性和膽管癌相關(guān)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(guān)基因甲基化研究進(jìn)展. 中國(guó)普外基礎(chǔ)與臨床雜志, 2011, 18(6): 672-675. doi: 復(fù)制

版權(quán)信息： ?四川大學(xué)華西醫(yī)院華西期刊社《中國(guó)普外基礎(chǔ)與臨床雜志》版權(quán)所有，未經(jīng)授權(quán)不得轉(zhuǎn)載、改編

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(nèi)外抑制膽管癌細(xì)胞生長(zhǎng)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(nèi)外抑制膽管癌細(xì)胞生長(zhǎng)的研究 [J]. 中華普通外科雜志, 2004, 19(5): 295297.