Microarray analysis of differentially expressed genes in ovarian and fallopian tube epithelium from risk‐reducing salpingo‐oophorectomies

Abstract

Mutations in the BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk-reducing salpingo-oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in the pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2- mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected together with five mutation-negative control patients undergoing salpingo-oophorectomy for benign indications. Microarray analysis of genome-wide gene expression was performed on ovarian and fallopian tube samples from the BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real-time polymerase chain reaction (qRT-PCR) in selected cases of RRSO samples and also in high grade serous carcinoma samples collected from patients with a BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when compared with controls, pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies.

Phase II Trial of Chemopreventive Effects of Levonorgestrel on Ovarian and Fallopian Tube Epithelium in Women at High Risk for Ovarian Cancer: An NRG Oncology Group/GOG Study

“…This is consistent with the surgicopathologic study of gynecologic cancers identified in >1,000 women who underwent risk reducing salpingooophorectomy, in which approximately equal proportions of ovarian and fallopian tube cancers were identified (44). It is further supported by the finding in genome-wide expression studies of numerous differentially expressed genes in both ovaries and fallopian tubes in women at high ovarian cancer risk (45). In addition, a recent series using detailed genomic analysis of serous tubal intraepithelial carcinomas (STICs), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases, demonstrated that although at least half of cases had a STIC as a precursor lesion, some STICs represented intraepithelial metastases to the fallopian tube (46).…”

Bilateral ovarian carcinomas differ in the expression of metastasis-related genes

“…Loss of ZFP36 expression has been associated with metastasis (20). A study by Veskimäe et al (38) identified ZFP36 as one of the most downregulated genes when the authors compared the gene expression in BRCA1 / 2 germline mutated tubal and ovarian tissues (removed by risk-reducing salpingo-oophorectomy) with that in healthy control tissues, thus supporting a role for ZFP36 in ovarian carcinogenesis.…”

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

“…Specifically, HRD exhibits a distinct core GEP [ 88 ]. Notably, in the context of gBRCA1* , even healthy fallopian tissue exhibits a specific GEP, suggesting an epigenome-modifying influence [ 89 , 90 ]. The partial divergence observed between BRCA1* and BRCA2* tumors probably relies on the pleiotropic function of BRCA1, which is not restricted to DSB management [ 91 , 92 ].…”