Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Abstract

Purpose:To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa. Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa. Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription^PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples. Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.

Prolonged Postovulatory Proinflammatory Signaling in the Fallopian Tube Epithelium May Be Mediated through a BRCA1/DAB2 Axis

“…Differential expression of NF-kB-regulated and inflammation-related genes In our initial study (2), FTE from 12 BRCA carriers and 12 control women were stratified by whether they were in the follicular phase or luteal phase (n ¼ 6 for each genotype and cycle phase). When analyzed as a group, the 6 luteal phase BRCA mutation carrier specimens partitioned more closely with HGSC and distant from the follicular phase and the control luteal phase samples.…”

“…We previously generated and compared gene expression profiles from laser capturemicrodissected nonmalignant fallopian tube epithelium (FTE) from BRCA1/2-mutation carriers (FTEb) and control patients at a baseline risk for adnexal HGSC (FTEn) to identify alterations predisposing to malignant transformation. Notably, FTEb samples collected during the luteal phase exhibited global molecular profiles more closely resembling that of HGSC than FTE collected during the follicular phase or from control patients (2). Despite a marked elevation of progesterone during the luteal phase, an overall difference in progesterone receptor signaling in FTE as a function of BRCA mutation status was not observed (3).…”

“…Preliminary reanalysis of our previously generated gene expression profiles (2) revealed that 110 of 630 (17.5%) of differentially expressed genes in BRCA1-mutated luteal phase FTE specimens found to cluster with HGSC on the basis of their global gene expression profiles [referred to as "FTEb(S)"] of known function are involved in inflammation/immune response. A gene of particular interest was tumor suppressor disabled homolog 2 (DAB2).…”

FGF18 as a prognostic and therapeutic biomarker in ovarian cancer

“…In addition to normal ovarian epithelium, FGF18 showed a likewise overexpression in HGSC over normal fallopian tube epithelium (FTE), an alternative precursor of serous ovarian cancer (14,15). In an independent data set consisting of 24 microdissected normal FTEs, 6 fallopian HGSCs and 7 ovarian HGSCs (14), FGF18 upregulation over normal FTEs was demonstrated in the 13 HGSCs (3.7-fold, P = 0.013) or 7 ovarian HGSCs (4.9-fold, P = 0.003).…”

Tumor microenvironment–associated modifications of alternative splicing

“…Recently, enriched cell populations generated by laser capture microdissection (LCM) have been useful in the identification of tumor-specific expression markers (Rogerson et al 2008;Tone et al 2008). In this study, we have used this approach to identify a highly specific group of cancer-associated ASEs by isolating tumors and their microenvironment and comparing them with reciprocal normal tissues.…”