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

Abstract

<div>Abstract<p><b>Purpose:</b> The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.</p><p><b>Experimental Design:</b> Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. <i>K</i>-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 <i>k</i>-means groups was evaluated using Cox proportional hazards models. Class prediction validated <i>k</i>-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.</p><p><b>Results:</b> 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 <i>N-cadherin</i> and <i>P-cadherin</i> 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.</p><p><b>Conclusion:</b> Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.</p></div>