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Clin Cancer Res. 2008 Aug 15;14(16):5198-208. doi: 10.1158/1078-0432.CCR-08-0196.

Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.

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1
Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia.

Abstract

PURPOSE:

The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.

EXPERIMENTAL DESIGN:

Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.

RESULTS:

Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.

CONCLUSION:

Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.

PMID:
18698038
DOI:
10.1158/1078-0432.CCR-08-0196
[Indexed for MEDLINE]
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