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

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.

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…GSEA analysis also showed overrepresentation of several cell cycle and DNA replication-related pathways (see Supplementary Table S2 for gene sets, enrichment scores, and P values). Similar with our recent analysis of a large cohort of serous invasive cancers (22), we also noted that a subset of invasive cancers had higher expression of markers associated with reactive myofibroblasts (reactive stroma; Fig. 1B and Supplementary Fig.…”

“…Constitutional DNA was available in all cases from peripheral blood, and informed consent was obtained from all patients. Expression array data from an additional 150 invasive serous ovarian carcinomas were included in the analyses; the characteristics of this cohort have previously been described (22). DNA from frozen tumor blocks and blood was extracted by the saltingout method, as described in ref.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…Ongoing molecular characterisation and genetic studies suggests that this model may be overly simplistic, with a number of subtypes being re-classified, or further divided into additional sub-groups [8,9,7,10]. These new subtypes demonstrate different genetic lesions and transcriptional profiles, chemo-sensitivity, and survival rates, indicating a need to incorporate this information into treatment plans for ovarian cancer.…”

Origin of carcinoma associated fibroblasts

“…[63][64][65][66][67][68][69][70][71] These genes include classical cancer stroma markers that reportedly may promote oncogenic potential of adjacent epithelia. 2,3,[72][73][74] This is possibly due to the late presentation with carcinoma disease in human life span. Diseases that present in individuals at post reproductive age, are not expected to be selected against in human evolution.…”