Abstract
Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.
Highlights
IntroductionThere is currently strong evidence to support that most high grade serous carcinoma (HGSC), the most common and aggressive ovarian cancer, arise from the fallopian tube epithelia (FTE) [1,2,3,4].The human fallopian tube has three major anatomical regions: the distal end (fimbria), the ampulla and the isthmic region (proximal to the uterus)
There is currently strong evidence to support that most high grade serous carcinoma (HGSC), the most common and aggressive ovarian cancer, arise from the fallopian tube epithelia (FTE) [1,2,3,4].The human fallopian tube has three major anatomical regions: the distal end, the ampulla and the isthmic region
A t-distributed stochastic neighbor embedding map (t-SNE) analysis showed cases broadly clustered according to ovarian cycle phase (Figure 2A, Figure S1B)
Summary
There is currently strong evidence to support that most high grade serous carcinoma (HGSC), the most common and aggressive ovarian cancer, arise from the fallopian tube epithelia (FTE) [1,2,3,4].The human fallopian tube has three major anatomical regions: the distal end (fimbria), the ampulla and the isthmic region (proximal to the uterus). Pregnancy and breast-feeding are significant protective factors [17,19] These risk factors are related to the number of ovulatory cycles. Latent precursor lesions which include the p53 signature and precancerous lesions such as serous tubal intraepithelial lesions (STIC) have been identified in the fallopian tube epithelium using the SEE-FIM protocol [20,21,22,23]. These lesions are predominantly found in the fimbriated end of the tube and are associated with greater risk of developing HGSC [24]. There are ongoing studies using radical fimbriectomy (removal of fimbria and tubo-ovarian junction), in BRCA1/2 mutation carriers to determine the number of ovarian or primary serous peritoneal carcinoma occurring between fimbriectomy and menopause (NCT01608074)
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