Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior.
BMC Cancer
; 12: 260, 2012 Jun 19.
Article
em En
| MEDLINE
| ID: mdl-22712570
ABSTRACT
BACKGROUND:
Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival.METHODS:
Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed.RESULTS:
Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear ß-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and CHR = 8.56(2.53-29.01); Dukes B,C and DHR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes.CONCLUSIONS:
We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Estromais
/
Neoplasias do Colo
/
Adenocarcinoma Mucinoso
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
BMC Cancer
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Espanha