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Abstract
BackgroundIrregular menstruation is clinically associated with an increased risk for ovarian cancer and disease-related mortality. This relationship remains poorly understood, and a mechanism explaining it has yet to be described.MethodsOvarian tissues from women with polycystic ovary syndrome (PCOS) and regular menstruation (n = 10) or irregular menstruation (n = 10) were subjected to DNA methylation sequencing, real-time PCR array, whole-exome sequencing, and bioinformatics analysis.ResultsWe demonstrated that ovarian tissue from PCOS patients with irregular menstruation displayed global DNA hypomethylation, as well as hypomethylation at several functionally and oncologically significant regions. Furthermore, we showed that several cancer-related genes were aberrantly expressed in ovarian tissue from patients with irregular menstruation, and that their mRNA and microRNA profiles shared appreciable levels of coincidence with those from ovarian cancer tissue. We identified multiple point mutations in both the BRCA1 and MLH1 genes in patients with irregular menstruation, and predicted the potential pathogenicity of these mutations using bioinformatics analyses.ConclusionsDue to the nature of ovarian cancer, it is important to broaden our understanding of the pathogenesis and risk factors of the disease. Herein, we provide the first description of a genetic and epigenetic basis for the clinical relationship between irregular menstruation and an increased risk for ovarian cancer.
Highlights
Irregular menstruation is clinically associated with an increased risk for ovarian cancer and diseaserelated mortality
Promoter methylation was significantly lower in the irregular menstruation group compared to the control; both high and low-CpG density promoters, two groups that differ in their rate of mutation [13], showed the same trend (Fig. 1b)
We further examined intronic and extronic regions, the 5′ and 3′UTRs, intergenic region, as well as CpG islands (CGI) and CGI shores; all showed hypomethylation in the irregular menstruation group compared to the control (Fig. 1a)
Summary
Irregular menstruation is clinically associated with an increased risk for ovarian cancer and diseaserelated mortality. This relationship remains poorly understood, and a mechanism explaining it has yet to be described. Current literature gives no clear consensus on the association between these two conditions, and suggests that the relationship is multifactorial and stratified among different subtypes of ovarian cancer. These findings highlight the importance of continued investigation into the relationship between ovarian cancer and PCOS
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