Biologia molecular

Solo disponible en BuenasTareas
  • Páginas : 11 (2505 palabras )
  • Descarga(s) : 0
  • Publicado : 7 de octubre de 2010
Leer documento completo
Vista previa del texto
RevIeWS
Mismatch repair deficient colorectal cancer in the era of personalized treatment
Madeleine Hewish, Christopher J. Lord, Sarah A. Martin, David Cunningham and Alan Ashworth
abstract | The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reducedtoxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how adeficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.
Hewish, M. et al. Nat. Rev. Clin. Oncol. 7, 197–208 (2010); published online 23February 2010; doi:10.1038/nrclinonc.2010.18

Introduction

Colorectal cancer (CrC) is the third most common cancer type and the third leading cause of cancer deaths in developed countries. more than 145,000 people are diagnosed with CrC each year in the us alone.1 it is understandable, therefore, that major efforts have been directed at dissecting the underlying pathogenesis of this disease.Pivotal to these studies has been the growing appreciation of the genetic heterogeneity that exists within CrC. one of the most studied genotypic subtypes of CrC is that characterized by a deficient mismatch repair (dmmr) pathway, usually found in combination with microsatellite instability (msi). this review provides some background to dmmr in CrC before outlining its impact on standard management.we also discuss how the dmmr phenotype could be exploited in developing novel therapeutic strategies. these issues are currently of renewed interest due to the publication of new clinical data that suggests a differential response to chemotherapeutics in the dmmr population.

The mismatch repair system

the Dna content of each cell is replicated prior to cell division. this is an error-proneprocess that may lead to the introduction of incorrect Dna bases into newly synthesized Dna (base-base mismatches) or the formation of unmatched Dna loops (insertion–deletion loops).
competing interests C. J. Lord and A. Ashworth declare an association with the following organization: KuDOS-AstraZeneca in association with The Institute of Cancer Research. C. J. Lord, S. A. Martin and A. Ashworthdeclare an association with the following organization: CRUK in association with The Institute of Cancer Research. D. Cunningham declares an association with the following organization: The Royal Marsden NHS Foundation Trust. See the article online for full details of the relationships. M. Hewish declares no competing interests.

if left unrepaired, these errors may result in permanent mutationsthat could change the behavior of a cell and foster tumorigenesis. Cells have evolved a number of Dna repair mechanisms to counter these errors, including the mmr system. in brief, this pathway involves four key processes: recognition of the erroneous bases or insertion–deletion loops, excision of these lesions, substitution of the lesion with the correct sequence, and religation of the Dna(Figure 1). instrumental to this process are the two protein dimer complexes hmuts and hmutl. the initial recognition of mismatches is performed by hmuts, which is found in two major forms, as hmutsα (a hmsH2/hmsH6 dimer) or hmutsβ (a hmsH2/hmsH3 dimer). hmutsα recognizes base-base mismatches and short insertion–deletion loops, whereas hmutsβ detects larger mismatches. when hmuts binds to a Dna lesion...
tracking img