Submit
Search
Submit
Menu

  • Information

  • References

  • Contents

  • [1]KK Ciombor, C Wu, RM Goldberg: Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med 66, 83-95 (2015)

  • [2]E Costello, W Greenhalf, JP Neoptolemos: New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol 9, 435-444 (2012)

  • [3]F De Vita, N Di Martino, A Fabozzi, MM Laterza, J Ventriglia, B Savastano, A Petrillo, V Gambardella, V Sforza, L Marano, A Auricchio, G Galizia, F Ciardiello, M Orditura M: Clinical management of advanced gastric cancer: the role of new molecular drugs. World J Gastroenterol 20, 14537-14558 (2014)

  • [4]L Fornaro, C Vivaldi, C Caparello, R Sacco, V Rotella, G Musettini, S Luchi, EE Baldini, A Falcone, G Masi: Dissecting signalling pathways in hepatocellular carcinoma: toward innovative medical treatment options. Future Oncol 10, 285-304 (2014)

  • [5]SB Baylin, PA Jones: A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 11, 726-734 (2011)

  • [6]M Toyota, N Ahuja, M Ohe-Toyota, JG Herman, SB Baylin, JP Issa: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96, 8681-8686 (1999)

  • [7]S Ogino, K Nosho, GJ Kirkner, T Kawasaki, JA Meyerhardt, MLoda, EL Giovannucci, CS Fuchs: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58, 90-96 (2009)

  • [8]AE Pegg: Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50, 6119-6129 (1990)

  • [9]M Esteller, SR Hamilton, PC Burger, SB Baylin, JG Herman: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59, 793-797 (1999)

  • [10]JG Herman, SB Baylin. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349, 2042-2054 (2003)

  • [11]S de Vogel, MP Weijenberg, JG Herman, KA Wouters, AF de Goeij, PA van den Brandt, AP de Bruïne, M van Engeland: MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events. Ann Oncol 20, 1216-1222 (2009)

  • [12]M Esteller, M Toyota, M Sanchez-Cespedes, G Capella, MA Peinado, DN Watkins, JP Issa, D Sidransky, SB Baylin, JG Herman: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60, 2368-2371 (2000)

  • [13]J Fahrer, B Kaina: O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer. Carcinogenesis 34, 2435-2442 (2013)

  • [14]JA Oliver, R Ortiz, C Melguizo, PJ Alvarez, J Gómez-Millán, J Prados: Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. BMC Cancer 14, 511 (2014)

  • [15]T Fukushima, H Takeshima, H Kataoka: Anti-glioma therapy with temozolomide and status of the DNA-repair gene MGMT. Anticancer Res 29, 4845-4854 (2009)

  • [16]SL Gerson: MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4, 296-307 (2004)

  • [17]ME Hegi, AC Diserens, T Gorlia, MF Hamou, N de Tribolet, M Weller, JM Kros, JA Hainfellner, W Mason, L Mariani, JE Bromberg, P Hau, RO Mirimanoff, JG Cairncross, RC Janzer, R Stupp: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352, 997-1003 (2005)

  • [18]F Içli, A Arican, F Cay, H Akbulut, D Dinçol, H Karaoğuz, A Demirkazik: Phase II study of cisplatin and dacarbazine for metastatic colorectal carcinoma resistant to 5-fluorouracil. Oncology 56, 297-300 (1999)

  • [19]H Akbulut, F Icli, B Yalcin, A Demirkazik, H Onur, A Buyukcelik, G Utkan: Activity of irinotecan, cisplatin and dacarbazine (CPD) combination in previously treated patients with advanced colorectal carcinoma. Exp Oncol 26, 149-152 (2004)

  • [20]OA Khan, M Ranson, M Michael, I Olver, NC Levitt, P Mortimer, AJ Watson, GP Margison, R Midgley, MR Middleton: A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer. Br J Cancer 98, 1614-1618 (2008)

  • [21]DD Von Hoff, JJ Jr Stephenso, P Rosen, DM Loesch, MJ Borad, S Anthony, G Jameson, S Brown, N Cantafio, DA Richards, TR Fitch, E Wasserman, C Fernandez, S Green, W Sutherland, M Bittner, A Alarcon, D Mallery, R Penny: Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol 28, 4877-4883 (2010)

  • [22]E Shacham-Shmueli, A Beny, R Geva, A Blachar, A Figer, D Aderka D: Response to temozolomide in patients with metastatic colorectal cancer with loss of MGMT expression: a new approach in the era of personalized medicine? J Clin Oncol 29, e262-265 (2011)

  • [23]A Amatu, A Sartore-Bianchi, C Moutinho, A Belotti, K Bencardino, G Chirico, A Cassingena, F Rusconi, A Esposito, M Nichelatti, M Esteller, S Siena: Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin Cancer Res 19, 2265-2272 (2013)

  • [24]D Hochhauser, R Glynne-Jones, V Potter, C Grávalos, TJ Doyle, K Pathiraja, Q Zhang, L Zhang, EA Sausville: A phase II study of temozolomide in patients with advanced aerodigestive tract and colorectal cancers and methylation of the O6-methylguanine-DNA methyltransferase promoter. Mol Cancer Ther 12, 809-818 (2013)

  • [25]F Pietrantonio, F Perrone, F de Braud, A Castano, C Maggi, I Bossi, A Gevorgyan, P Biondani, M Pacifici, A Busico, M Gariboldi, F Festinese, E Tamborini, M Di Bartolomeo: Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation. Ann Oncol 25, 404-408 (2014)

  • [26]A Sato, J Sunayama, K Matsuda, S Seino, K Suzuki, E Watanabe, K Tachibana, A Tomiyama, T Kayama, C Kitanaka: MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis. Stem Cells 29, 1942-1951 (2011)

  • [27]F Pietrantonio, F de Braud, C Maggi, M Milione, R Iacovelli, A Castano, F Perrone, I Bossi, F Ricchini, S Pusceddu, G Leone, F Dominoni, G Saibene, M Di Bartolomeo: Dose-dense temozolomide (TMZ) in patients with advanced chemorefractory colorectal cancer (CRC) and MGMT promoter methylation. Ann Oncol 25 (suppl 2), ii98 (P-0267) (2014)

  • [28]V Quillien, A Lavenu, M Sanson, M Legrain, P Dubus, L Karayan-Tapon, J Mosser, K Ichimura, D Figarella-Branger: Outcome-based determination of optimal pyrosequencing assay for MGMT methylation detection in glioblastoma patients. J Neurooncol 116, 487-496 (2014)

  • [29]V Quillien, A Lavenu, L Karayan-Tapon, C Carpentier, M Labussière, T Lesimple, O Chinot, M Wager, J Honnorat, S Saikali, F Fina, M Sanson, D Figarella-Branger: Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, methylight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients. Cancer 118, 4201-4211 (2012)

  • [30]S Ogino, A Hazra, GJ Tranah, GJ Kirkner, T Kawasaki, K Nosho, M Ohnishi, Y Suemoto, JA Meyerhardt, DJ Hunter, CS Fuchs: MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis 28, 1985-1990 (2007)

  • [31]NJ Hawkins, JH Lee, JJ Wong, CT Kwok, RL Ward, MP Hitchins: MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa. Mod Pathol 22, 1588-1599 (2009)

  • [32]M van Engeland, S Derks, KM Smits, GA Meijer, JG Herman: Colorectal cancer epigenetics: complex simplicity. J Clin Oncol 29, 1382-1391 (2011)

  • [33]K Suzuki, I Suzuki, A Leodolter, S Alonso, S Horiuchi, K Yamashita, M Perucho: Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell 9, 199-207 (2006)

  • [34]F Crea, S Nobili, E Paolicchi, G Perrone, C Napoli, I Landini, R Danesi, E Mini: Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies. Drug Resist Updat 14:280-296 (2011)

  • [35]I Garrido-Laguna, KA McGregor, M Wade, J Weis, W Gilcrease, L Burr, R Soldi, L Jakubowski, C Davidson, G Morrell, JD Olpin, K Boucher, D Jones, S Sharma: A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer. Invest New Drugs 31, 1257-1264 (2013)

  • [36]D Santini, B Vincenzi, R Addeo, C Garufi, G Masi, M Scartozzi, A Mancuso, AM Frezza, O Venditti, M Imperatori, G Schiavon, G Bronte, G Cicero, F Recine, E Maiello, S Cascinu, A Russo, A Falcone, G Tonini: Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Ann Oncol 23, 2313-2318 (2012)

  • [37]A Goel, CR Boland: Epigenetics of colorectal cancer. Gastroenterology 143, 1442-1460 (2012)

  • [38]MG Fakih, A Groman, J McMahon, G Wilding, JR Muindi: A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer. Cancer Chemother Pharmacol 69, 743-751 (2012)

  • [39]KM Smits, V Melotte, HE Niessen, L Dubois, C Oberije, EG Troost, MH Starmans, PC Boutros, M Vooijs, M van Engeland, P Lambin: Epigenetics in radiotherapy: where are we heading? Radiother Oncol 111, 168-177 (2014)

  • [40]A Avallone, MC Piccirillo, P Delrio, B Pecori, E Di Gennaro, L Aloj, F Tatangelo, V D’Angelo, C Granata, E Cavalcanti, N Maurea, P Maiolino, F Bianco, M Montano, L Silvestro, M Terranova Barberio, MS Roca, M Di Maio, P Marone, G Botti, A Petrillo, G Daniele, S Lastoria, VR Iaffaioli, G Romano, C Caracò, P Muto, C Gallo, F Perrone, A Budillon A: Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid - short RadioTherapy - rectum 3rd trial). BMC Cancer 14, 875 (2014)

  • [41]JJ Wheler, F Janku, GS Falchook, TL Jackson, S Fu, A Naing, AM Tsimberidou, SL Moulder, DS Hong, H Yang, SA Piha-Paul, JT Atkins, G Garcia-Manero, R Kurzrock: Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. Cancer Chemother Pharmacol 73, 495-501 (2014)

  • [42]C Kang, JJ Song, J Lee, MY Kim: Epigenetics: an emerging player in gastric cancer. World J Gastroenterol 20, 6433-6447 (2014)

  • [43]DQ Calcagno, CO Gigek, ES Chen, RR Burbano, Mde. A Smith: DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol 19, 1182-1192 (2013)

  • [44]J Nakamura, T Tanaka, Y Kitajima, H Noshiro, K Miyazaki: Methylation-mediated gene silencing as biomarkers of gastric cancer: a review. World J Gastroenterol 20, 11991-12006 (2014)

  • [45]WK Leung, KF To, ES Chu, MW Chan, AH Bai, EK Ng, FK Chan, JJ Sung JJ: Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Br J Cancer 92, 2190-2194 (2005)

  • [46]K Hibi, M Sakata, K Yokomizo, YH Kitamura, K Sakuraba, A Shirahata, T Goto, H Mizukami, M Saito, K Ishibashi, G Kigawa, H Nemoto, Y Sanada: Methylation of the MGMT gene is frequently detected in advanced gastric carcinoma. Anticancer Res 29, 5053-5055 (2009)

  • [47]J Jin, L Xie, CH Xie, YF Zhou. Aberrant DNA methylation of MGMT and hMLH1 genes in prediction of gastric cancer. Genet Mol Res 13, 4140-4145 (2014)

  • [48]C Yoo, MH Ryu, YS Na, BY Ryoo, CW Lee, J Maeng, SY Kim, DH Koo, I Park, YK Kang: Phase I and pharmacodynamic study of vorinostat combined with capecitabine and cisplatin as first-line chemotherapy in advanced gastric cancer. Invest New Drugs 32, 271-278 (2014)

  • [49]I Regel, L Merkl, T Friedrich, E Burgermeister, W Zimmermann, H Einwächter, K Herrmann, R Langer, C Röcken, R Hofheinz, R Schmid, MP Ebert: Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2. Gastroenterology 143, 99-109 (2012)

  • [50]Y Su, L Yin, R Liu, J Sheng, M Yang, Y Wang, E Pan, W Guo, Y Pu, J Zhang, G Liang: Promoter methylation status of MGMT, hMSH2, and hMLH1 and its relationship to corresponding protein expression and TP53 mutations in human esophageal squamous cell carcinoma. Med Oncol 31, 784 (2014)

  • [51]R Hasina, M Surati, I Kawada, Q Arif, GB Carey, R Kanteti, AN Husain, MK Ferguson, EE Vokes, VM Villaflor, R Salgia: O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. J Carcinog 12, 20 (2013)

  • [52]AL McCleary-Wheeler, GA Lomberk, FU Weiss, G Schneider, M Fabbri, TL Poshusta, NJ Dusetti, S Baumgart, JL Iovanna, V Ellenrieder, R Urrutia, ME Fernandez-Zapico: Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett 328, 212-221 (2013)

  • [53]D Neureiter, T Jäger, M Ocker, T Kiesslich: Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. World J Gastroenterol 20, 7830-7848 (2014)

  • [54]H Wang, Q Cao, AZ Dudek: Phase II study of panobinostat and bortezomib in patients with pancreatic cancer progressing on gemcitabine-based therapy. Anticancer Res 32, 1027-1031 (2012)

  • [55]JP Hamilton: Epigenetic mechanisms involved in the pathogenesis of hepatobiliary malignancies. Epigenomics 2, 233-243 (2010)

  • [56]Y Koga, Y Kitajima, A Miyoshi, K Sato, K Kitahara, H Soejima, K Miyazaki: Tumor progression through epigenetic gene silencing of O(6)-methylguanine-DNA methyltransferase in human biliary tract cancers. Ann Surg Oncol 12, 354-363 (2005)

  • [57]V Baradari, M Höpfner, A Huether, Schuppan D, H Scherübl: Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong anti-proliferative action in human cholangiocarcinoma cells. World J Gastroenterol 13, 4458-4466 (2007)

  • [58]S Nakagawa, Y Sakamoto, H Okabe, H Hayashi, D Hashimoto, N Yokoyama, R Tokunaga, K Sakamoto, H Kuroki, K Mima, T Beppu, H Baba: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol Rep 31, 983-988 (2014)

  • [59]L Ma, MS Chua, O Andrisani, S So: Epigenetics in hepatocellular carcinoma: an update and future therapy perspectives. World J Gastroenterol 20, 333-345 (2014)

  • [60]IP Pogribny, I Rusyn: Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. Cancer Lett 342, 223-230 (2014)

  • [61]W Yeo, HC Chung, SL Chan, LZ Wang, R Lim, J Picus, M Boyer, FK Mo, J Koh, SY Rha, EP Hui, HC Jeung, JK Roh, SC Yu, KF To, Q Tao, BB Ma, AW Chan, JH Tong, C Erlichman, AT Chan, BC Goh: Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phaseI/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortiumand the Cancer Therapeutics Research Group. J Clin Oncol 30, 3361-3367 (2012)

  • [62]RL Fine, AP Gulati, BA Krantz, RA Moss, S Schreibman, DA Tsushima, KB Mowatt, RD Dinnen, Y Mao, PD Stevens, B Schrope, J Allendorf, JA Lee, WH Sherman, JA Chabot: Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 71, 663-670 (2013)

  • [63]G Reynés, C Balañá, O Gallego, L Iglesias, P Pérez, JL García: A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma. Anticancer Drugs 25, 717-722 (2014) No DOI found

Article Metrics

  • Information

  • Download

  • Contents

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

1 Jan 2016Review

Pharmacoepigenetics in gastrointestinal tumors: MGMT methylation and beyond

Lorenzo Fornaro 1,*, Caterina Vivaldi 1, Chiara Caparello 1, Gianna Musettini 1, Editta Baldini 2, Gianluca Masi 1, Alfredo Falcone 1
Affiliations
Article Info

1 Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

2 Unit of Oncology, Department of Oncology, Azienda USL2, Lucca, Italy

*Author to whom correspondence should be addressed.

 

Abstract

Epigenetic mechanisms are involved in gastrointestinal (GI) cancer pathogenesis. Insights into the molecular basis of GI carcinogenesis led to the identification of different epigenetic pathways and signatures that may play a role as therapeutic targets in metastatic colorectal cancer (mCRC) and non-colorectal GI tumors. Among these alterations, O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation is the most investigated biomarker and seems to be an early and frequent event, at least in CRC. Loss of expression of MGMT as a result of gene promoter methylation has been associated with interesting activity of alkylating agents in mCRC. However, the optimal methods for the definition of the MGMT status and additional predictive factors beyond MGMT in GI malignancies are lacking. Here we review the current role of MGMT methylation and other epigenetic alterations as potential treatment targets in GI tumors.

Keywords

  • lkylating Agents
  • Braf
  • Cancer Epigenetics
  • Colorectal Cancer
  • Gastrointestinal Tumors
  • Methylation
  • MGMT
  • RAS
  • Review

References