Oncology and Pharmacogenomics Insights in Polycystic Ovary Syndrome: An Integrative Analysis

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Epidemiological findings revealed that women with PCOS are prone to develop certain cancer types due to their shared metabolic and endocrine abnormalities. However, the mechanism that relates PCOS and oncogenesis has not been addressed. Herein, in this review article the genomic status, transcriptional and protein profiles of 264 strongly PCOS related genes (PRG) were evaluated in endometrial cancer (EC), ovarian cancer (OV) and breast cancer (BC) exploring oncogenic databases. The genomic alterations of PRG were significantly higher when compared with a set of non-diseases genes in all cancer types. PTEN had the highest number of mutations in EC, TP53, in OC, and FSHR, in BC. Based on clinical data, women older than 50 years and Black or African American females carried the highest ratio of genomic alterations among all cancer types. The most altered signaling pathways were p53 in EC and OC, while Fc epsilon RI in BC. After evaluating PRG in normal and cancer tissue, downregulation of the differentially expressed genes was a common feature. Less than 30 proteins were up and downregulated in all cancer contexts. We identified 36 highly altered genes, among them 10 were shared between the three cancer types analyzed, which are involved in the cell proliferation regulation, response to hormone and to endogenous stimulus. Despite limited PCOS pharmacogenomics studies, 10 SNPs are reported to be associated with drug response. All were missense mutations, except for rs8111699, an intronic variant characterized as a regulatory element and presumably binding site for transcription factors. In conclusion, in silico analysis revealed key genes that might participate in PCOS and oncogenesis, which could aid in early cancer diagnosis. Pharmacogenomics efforts have implicated SNPs in drug response, yet still remain to be found.

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

“…PCOS is the most probable cause of anovulation-mediated infertility, striking about 2-26% of women of the 18-44 age group [1,2]. PCOS is considered a highrisk factor for several metabolic complications, such as MetS (metabolic syndrome), CVD (cardiovascular disease), T2DM (type 2 diabetes mellitus), and IR (insulin resistance), with a recent noticeable increase in cases of endometrial cancer [3]. Notwithstanding the decades of intensive research, the exact molecular mechanism of PCOS pathogenesis is still obscure.…”

Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment

“…The majority of women with PCOS manifest multiple metabolic features including obesity, insulin resistance (IR), hyperlipidemia and hyperandrogenism [19,20]. PCOS results in an increased risk of developing metabolic disease (type 2 diabetes, non-alcoholic fatty liver disease [NAFLD] and metabolic syndrome), cardiovascular disease, cancer, a wide array of pregnancy complications (deep venous thrombosis, pre-eclampsia, gestational diabetes [GDM], macrosomia, growth restriction, miscarriage, stillbirth and preterm labor) and psychological problems (anxiety, depression) [6,[21][22][23][24][25]. PCOS is part of a cluster of inter-related metabolic conditions and makes a significant contribution to the chronic disease epidemic.…”

Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms that Disturb the Hallmarks of Health in Polycystic Ovary Syndrome

“…Women affected with PCOS present with a wide variety of symptoms (menstrual disturbance, acne, hirsutism, alopecia, subfertility, anxiety and depression) that reflect the underlying multisystem pathophysiology (8)(9)(10). Women with PCOS have an increased risk of pregnancy complications (deep venous thrombosis, pre-eclampsia, macrosomia, growth restriction, miscarriage, stillbirth and preterm labor) (11), psychological problems (anxiety, depression) (12), and can progress to a range of other metabolic-related conditions (obesity, gestational diabetes, type 2 diabetes (T2DM), metabolic-associated fatty liver disease, chronic kidney disease, metabolic syndrome, cardiovascular disease, and cancer) (13)(14)(15)(16). The population attributable risk of PCOS to T2DM alone has been estimated at 19-28% of women of reproductive age (17).…”