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

RW Tothill, AV Tinker, J George, R Brown, SB Fox… - Clinical cancer …, 2008 - AACR
RW Tothill, AV Tinker, J George, R Brown, SB Fox, S Lade, DS Johnson, MK Trivett…
Clinical cancer research, 2008AACR
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 …
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.
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