Defective DNA mismatch repair determines a characteristic transcriptional profile in proximal colon cancers.
Gastroenterology
; 129(3): 1047-59, 2005 Sep.
Article
en En
| MEDLINE
| ID: mdl-16143142
ABSTRACT
BACKGROUND & AIMS:
Colon cancers with defective DNA mismatch repair (MMR) have peculiar molecular, pathologic, and clinical features, including high-level microsatellite instability, conspicuous lymphocytic infiltration, preferential location in the proximal colon, and better prognosis. Our aim was to characterize the transcriptional profile of this colon cancer subset.METHODS:
An oligonucleotide microarray containing 12,625 probes was used to evaluate gene expression in 25 proximal colon cancers, 10 samples of normal colon mucosa, and 14 colon cancer cell lines. Transcriptional profiles of MMR-deficient cancers and cell lines were compared with those of their MMR-proficient counterparts.RESULTS:
Unsupervised analysis of microarray data showed that MMR status exerts a predominant influence on the gene expression profile of proximal colon cancers. Hierarchical clustering divided the cancers into 2 groups corresponding almost perfectly with their MMR status. Supervised analysis identified numerous gene expression changes that represent a genetic signature of MMR-deficient colon cancers. Changes in genes involved in apoptosis and the immune response were consistent with the better prognosis of MMR-deficient cancers. In MMR-deficient cancers and cell lines, 4-1BBL, a crucial gene in the anti-tumor immune response, was, respectively, 2.4 and 6.0 times more expressed than in their MMR-proficient counterparts. This difference was confirmed by quantitative reverse-transcription polymerase chain reaction and flow cytometric assessment of 4-1BBL protein expression in colon cancer cell lines. Our analysis also showed novel possible gene targets of microsatellite instability.CONCLUSIONS:
MMR inactivation produces distinct changes in the cellular messenger RNA pool, which is consistent with a unique tumorigenesis pathway.
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Banco de datos:
MEDLINE
Asunto principal:
Transcripción Genética
/
Proteínas Nucleares
/
Neoplasias del Colon
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Disparidad de Par Base
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Perfilación de la Expresión Génica
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Reparación del ADN
/
Proteínas de Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Año:
2005
Tipo del documento:
Article