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Am J Cancer Res. 2014 Jan 15;4(1):61-72. eCollection 2014.

Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma.

Author information

1
College of Medicine, University of Arizona Tucson, AZ, USA.
2
Mel and Enid Zuckerman College of Public Health, University of Arizona Tucson, AZ, USA.
3
College of Medicine, University of Arizona Tucson, AZ, USA ; Department of Obstetrics and Gynecology, University of Arizona Tucson, AZ, USA.
4
Department of Pathology, University of Jordan Amman, Jordan ; Department of Pathology, University of Arizona Tucson, AZ, USA.
5
University of Arizona Cancer Center Tucson, AZ, USA.
6
College of Medicine, University of Arizona Tucson, AZ, USA ; University of Arizona Cancer Center Tucson, AZ, USA ; Department of Pathology, University of Arizona Tucson, AZ, USA.
7
College of Medicine, University of Arizona Tucson, AZ, USA ; Department of Obstetrics and Gynecology, University of Arizona Tucson, AZ, USA ; University of Arizona Cancer Center Tucson, AZ, USA.

Abstract

INTRODUCTION:

BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways.

METHODS:

A prospective study of 47 HR women (40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy and 48 LR controls undergoing salpingo-oophorectomy was performed. Ovarian/tubal tissues were harvested. Immunohistochemical analysis of candidate proteins CSF-1, CSF-1R, ErbB4 is presented, with scores separately analyzed in epithelium and stroma, in ampulla, fimbria, ovary, and ovarian endosalpingiosis (ES). Comparison was performed between HR and LR groups.

RESULTS:

Elevated levels of CSF-1 (p=0.005) or ErbB4 (p=0.005) in the ovarian epithelium, or ErbB4 (p=0.005) in the ovarian stroma, were significantly associated with both the HR status and carrying a BRCA mutation, as was nuclear ErbB4 staining. Ovarian ES, an entity which likely derives from the tubal mucosal epithelium, was also associated with HR (p=0.038) and BRCA mutation status (p=0.011). Among the BRCA carriers only, markers also found association when present in the tube as well as in ovarian ES (p < 0.05). ROCs were generated including in the regression model both CSF-1 and ErbB4 expression levels. A model including CSF-1 in ovarian epithelium, ErbB4 in ovarian stroma, and younger age achieves AUC=0.87 (73% sensitivity, 93% specificity) of detection of the HR status. In BRCA carriers, CSF-1 in ovarian epithelium alone achieves AUC=0.85.

CONCLUSIONS:

Our data suggest that elevated levels of CSF-1/ErbB4 in the adnexae correlate with HR/BRCA carrier status. CSF-1/CSF-1R signaling is active in ovarian cancer progression; our data suggests a role in its initiation. ErbB4, in particular nuclear ErbB4, may have a role in tumor initiation as well. Ovarian ES, an entity which may represent a latent precursor to low-grade pelvic serous carcinomas, was surprisingly associated with both HR status and the BRCA carrier cohort. In line with these findings, both ErbB4 and CSF-1R expression in ovarian ES correlated with carrying a BRCA mutation. This analysis, which needs to be validated, indirectly suggests a potential link between ovarian ES and the development of pelvic serous carcinoma in women who are BRCA mutation carriers.

KEYWORDS:

CSF-1; ErbB4; endosalpingiosis; high-risk

PMID:
24482739
PMCID:
PMC3902233

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