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World J Gastrointest Oncol. Mar 15, 2010; 2(3): 151-158
Published online Mar 15, 2010. doi: 10.4251/wjgo.v2.i3.151
Differential colorectal carcinogenesis: Molecular basis and clinical relevance
Alberto Morán, Paloma Ortega, Carmen de Juan, Tamara Fernández-Marcelo, Cristina Frías, Andrés Sánchez-Pernaute, Antonio José Torres, Eduardo Díaz-Rubio, Pilar Iniesta, Manuel Benito
Alberto Morán, Paloma Ortega, Carmen de Juan, Tamara Fernández-Marcelo, Cristina Frías, Pilar Iniesta, Manuel Benito, the second Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University, 28040-Madrid, Spain
Andrés Sánchez-Pernaute, Antonio José Torres, Surgery Service II, Clínico San Carlos Hospital, 28040-Madrid, Spain
Eduardo Díaz-Rubio, Oncology Service, Clínico San Carlos Hospital, 28040-Madrid, Spain
Author contributions: Morán A, de Juan C, Frías C, Ortega P and Fernández-Marcelo T performed the molecular analyses; Sánchez-Pernaute A and Torres AJ assessed the clinical correlations; Díaz-Rubio E was assessor of this work; Benito M directed and coordinated this work; Benito M, Iniesta P and Morán A were involved in writing the manuscript.
Supported by Grants from Ministerio de Sanidad y Consumo, FIS PI080033; Fundación de Investigación Médica Mutua Madrileña and RTICC RD06/0020/0021
Correspondence to: Manuel Benito, PhD, the second Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University, 28040-Madrid, Spain. benito@farm.ucm.es
Telephone: +34-91-3941777 Fax: +34-91-3941779
Received: March 19, 2009
Revised: August 24, 2009
Accepted: August 31, 2009
Published online: March 15, 2010
Abstract

Colorectal cancer (CCR) is one of the most frequent cancers in developed countries. It poses a major public health problem and there is renewed interest in understanding the basic principles of the molecular biology of colorectal cancer. It has been established that sporadic CCRs can arise from at least two different carcinogenic pathways. The traditional pathway, also called the suppressor or chromosomal instability pathway, follows the Fearon and Vogelstein model and shows mutation in classical oncogenes and tumour suppressor genes, such as K-ras, adenomatous polyposis coli, deleted in colorectal cancer, or p53. Alterations in the Wnt pathway are also very common in this type of tumour. The second main colorectal carcinogenesis pathway is the mutator pathway. This pathway is present in nearly 15% of all cases of sporadic colorectal cancer. It is characterized by the presence of mutations in the microsatellite sequences caused by a defect in the DNA mismatch repair genes, mostly in hMLH1 or hMSH2. These two pathways have clear molecular differences, which will be reviewed in this article, but they also present distinct histopathological features. More strikingly, their clinical behaviours are completely different, having the “mutator” tumours a better outcome than the “suppressor” tumours.

Keywords: Colorectal cancer; Microsatellite instability; Clinical outcome