Colorectal oncogenesis |
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| Authors: | Laurent-Puig P Agostini J Maley K |
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| Institution: | 1. AP–HM, Aix-Marseille university, department of medical oncology, 13005, Marseille, France;2. Institut Claudius Régaud, Cancer Research Center in Toulouse (CRCT), IUCT-oncopole, Inserm U1037, 31000, Toulouse, France;1. Université de Lille, institut de biochimie et de biologie moléculaire, oncogénétique moléculaire, CHU de Lille et Inserm UMR-S 1172, Lille, France;2. Centre Léon-Bérard, unité clinique d’oncologie génétique, Lyon, France;3. Université de Lyon 1, CNRS, LBBE UMR Villeurbanne, France;4. Department of Genetics, Rouen University Hospital and Inserm U1245, UNIROUEN, Normandy Centre for Genomic and Personalized Medicine (GPMCND), Rouen, France;5. CHU Rangueil, oncogénétique, institut universitaire du cancer - Oncopôle, et pôle hospitalo-universitaire des maladies digestives, Toulouse, France;6. AP–HP, hôpital Pitié Salpétrière, service de génétique, Paris, France;7. Université de Paris, unité d’oncogénétique clinique, gastroentérologie, AP–HP Centre (site Cochin), Paris, France;8. Université Claude-Bernard, hospices civils de Lyon, hépato-gastroentérologie, hôpital Edouard-Herriot, Lyon, France;9. Institut Paoli-Calmettes, laboratoire d’oncogénétique moléculaire, Marseille, France;10. Faculté de médecine de Clermont-Ferrand, laboratoire de biologie médicale OncoGènAuvergne et département d’oncogénétique, UMR Inserm 1240, Clermont-Ferrand, France;11. Gustave Roussy Cancer Campus, département de médecine oncologique, Villejuif, France;12. PSL Research University, Institut Curie, département de génétique, 26, rue d’Ulm, 75248 Paris cedex 05, France;1. Université de Bordeaux, Inserm UMR 1219, équipe Epicene, bâtiment ISPED – Case 11, 146, rue Léo-Saignat, 33076 Bordeaux cedex, France;2. Institut Bergonié, Inserm CIC-EC 1401, unité d’épidémiologie et de recherche cliniques, 229, cours de l’Argonne, 33000 Bordeaux, France;3. Université de Lille, faculté de médecine Henri-Warembourg, 2, avenue Eugène-Avinée, 59120 Loos, France;4. Centre Oscar-Lambret, 3, rue Frédéric-Combemale, 59000 Lille, France;1. Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK;2. Bristol Haematology and Oncology Centre, Bristol, UK |
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| Abstract: | Recent progress in the field of molecular biology has allowed us to identify at least two different molecular mechanisms implicated in colorectal carcinogenesis (CRC): chromosomal instability (CIN) and genetic instability. Even though the two molecular mechanisms differ, their signalling pathways, implicated in malignant transformation of colonic epithelial cells, appear to be similar. The most frequent group of CRC, which represents 80% of sporadic CRC, is characterized by allelic losses on the short arm of chromosome 17 and 8 and on the long arm of chromosome 5, 18 and 22. These allelic losses are associated with mutations in TP53, APC, SMAD2 and SMAD4 genes. All of these alterations are grouped under the phenotype CIN. A genetic instability termed MSI (microsatellite instability), which results from a mismatch repair (MMR) deficiency, appears in 12-15% of CRC cases. The presence of MMR deficiency leads to the accumulation of mutations in genes controlling cell cycle and apoptosis (TGFBRII, BAX or CASPASE5). More recently, the existence of a third phenotype was suggested. The main alteration associated with this group of tumors is the hypermethylation of the promoter region of numerous genes, leading to their inactivation. An activating mutation of BRAF is frequently associated with this phenotype. As described above, CRC shows genetic heterogeneity, however the consequences in terms of signalling pathway alterations are similar. For example, the activation of Wnt signalling pathways can result from the inactivation of the APC gene in the CIN phenotype or from an activating mutation in the β-catenin gene in MSI tumors. The inactivation of TGFβ pathways is also present in both tumor types and is driven by SMAD4, and more rarely by a SMAD2 inactivating mutation in CIN tumors, or by the existence of a frame-shift mutation occurring in a polyG coding track of the TGFβ (transforming growth factor) receptor type II in MSI tumors. The RAS-MAP kinase pathway is activated by KRAS mutations in CIN tumors or by BRAF mutations in MSI tumors. The p53 pathway is inactivated by TP53 inactivation in CIN tumors or by BAX inactivating mutations in MSI tumors. |
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| Keywords: | cancer colorectal phénotype CIN phénotype MSI phénotype CIMP colorectal cancer CIN phenotype MSI phenotype CIMP phenotype |
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