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Transformation of Human Fallopian Tube Stem Cells and high grade serous ovarian cancer

ABSTRACT: High-grade serous ovarian cancer (HGSOC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and oviducts in patients with BRCA mutations revealed that premalignant HGSC is found almost exclusively in the fallopian tube. To validate this notion, we cloned and transformed the fallopian tube stem cells (FTSC). We demonstrated that the tumors derived from the transformed fallopian tube stem cells (FTSCt) share the similar histological and molecular feature of high-grade serous cancer. In addition, a whole-genome transcriptome analysis comparing between FTSC, immortalized fallopian tube stem cells (FTSCi), and FTSCt showing a clear molecular progression, which is mimicked by the gene expression comparison between laser captured normal oviducts and HGSOC ( cancer and paired normal samples from 10 patients).

ORGANISM(S): Homo sapiens

PROVIDER: GSE69428 | GEO | 2015/09/29

SECONDARY ACCESSION(S): PRJNA285476

REPOSITORIES: GEO

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Project description:Mutations in 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 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 in comparison 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 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 high grade serous carcinoma samples collected from patients with BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when statistically compared to controls pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes were upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies. Both fallopian tube and ovarian samples were collected from each BRCA1/2 mutation carrier resulting in eighteen mutation positive adnexal samples. Both fallopian tube and ovarian control samples were collected from one control patient while either ovarian or fallopian tube sample was available from four control patients, respectively, resulting in 6 adnexal control samples. High quality RNA was available from nine BRCA1/2-mutation positive ovarian and eight BRCA1/2-mutation positive fallopian tube samples and from three control ovarian and three control fallopian tube samples.

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Transformation of Human Fallopian Tube Stem Cells and high grade serous ovarian cancer

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