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Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome

Authors' Affiliations: ¹ Peter MacCallum Cancer Center, ² Melbourne Pathology, ³ Victorian Cytology Service, ⁴ Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia; ⁵ Vancouver Cancer Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; ⁶ Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia; and ⁷ Queensland Institute for Medical Research, Brisbane, Australia

Requests for reprints: David Bowtell, Peter MacCallum Cancer Center, Locked Bag 1, A'Beckett Street, Melbourne, Victoria 8006, Australia. Phone: 61-3-96561356; Fax: 61-3-96561414; E-mail: d.bowtell{at}petermac.org.

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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