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

Clinical Cancer Research - Tập 14 Số 16 - Trang 5198-5208 - 2008
Richard W. Tothill1, Anna V. Tinker2, Joshy George3, Robert Brown4, Stephen B. Fox3, Stephen Lade5, Daryl Johnson3, Melanie Trivett3, Dariush Etemadmoghadam3, Bianca Locandro3, Nadia Traficante3, Sián Fereday3, Jillian A. Hung6, Yoke-Eng Chiew6, Izhak Haviv3, Dorota M. Gertig7, Anna deFazio6, David D.L. Bowtell3,8
1Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia.
25Vancouver Cancer Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
31Peter MacCallum Cancer Center,
42Melbourne Pathology,
57Queensland Institute for Medical Research, Brisbane, Australia
66Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia; and
73Victorian Cytology Service,
84Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia;

Tóm tắt

AbstractPurpose: 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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Clinical Cancer Research

Tập 14 Số 16

5198-5208

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