The Current State-or Lack Thereof-of Screening and Prevention for Gynecologic Malignancies for Patients With Lynch Syndrome.

Lynch syndrome (LS) is an autosomal dominant genetic disorder that results in an increased risk of ovarian and endometrial cancers. The aim of this paper was to explore the management of this risk through screening and prevention. Published materials and evidence were explored and summarized. This paper demonstrated that while there has been increased awareness and advances in the identification and diagnosis of patients with LS, recommendations for screening and prevention remain less evidence-based. In decisions of management of patients with LS, a shared decision-making model should be used considering individual patient goals.

Genetic Predisposition for Gynecologic Cancers.

Hereditary cancer syndromes (HCS) are responsible for up to 10% of all cancers. At present, the majority of cancer susceptibility testing is initiated after a cancer diagnosis. There exists a significant opportunity for primary care providers including general obstetrician-gynecologists to engage in hereditary cancer risk assessment through adequate family history evaluation, initiation of genetic testing, and following the recommendations of national organizations. Identifying hereditary cancer genes may prompt primary prevention efforts such as enhanced screening, prevention, or personalized care strategies. We will review the literature regarding the approach and assessment of the most common gynecologic HCS.

Special Issue: "Molecular Signatures of Gynecological Cancers-Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0".

Cancer of women's reproductive organs (gynecological cancers) and breast cancer affect women all over the world [...].

Targeting KRAS in gynecological malignancies.

Cervical, endometrial, and ovarian cancers stand prominently as the leading gynecological malignancies of the female reproductive system. The conventional therapeutic modalities for gynecological malignancies have predominantly encompassed surgery, chemotherapy, and radiotherapy. However, efficacy of these approaches remains limited in cases of relapse or drug resistance. KRAS is one of the most frequently mutated oncogenes in human cancers. The KRAS gene encodes a small guanosine triphosphatase protein that acts as a molecular switch for crucial intracellular signaling pathways. KRAS mutations are deeply involved in the occurrence and development of gynecological malignancies. The present review aims to expound upon the role of oncogenic KRAS as a biomarker, elucidating various therapeutic approaches under investigation targeting the KRAS pathway in gynecological tumors.

RNA modification regulators as promising biomarkers in gynecological cancers.

This review explores the evolving landscape of gynecological oncology by focusing on emerging RNA modification signatures as promising biomarkers for assessing the risk and progression of ovarian, cervical, and uterine cancers. It provides a comprehensive overview of common RNA modifications, especially m6A, and their roles in cellular processes, emphasizing their implications in gynecological cancer development. The review meticulously examines specific m6A regulators including "writers", "readers", and "erasers" associated with three gynecological cancer types, discussing their involvement in initiation and progression. Methodologies for detecting RNA modifications are surveyed, highlighting advancements in high-throughput techniques with high sensitivity. A critical analysis of studies identifying m6A regulators as potential biomarkers is presented, addressing their diagnostic or prognostic significance. Mechanistic insights into RNA modification-mediated cancer progression are explored, shedding light on molecular pathways and potential therapeutic targets. Despite current challenges, the review discusses ongoing research efforts, future directions, and the transformative possibility of RNA modifications on early assessment and personalized therapy in gynecological oncology.

The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy.

Gynecological cancers are the leading cause of malignancy-related death and disability in the world. These cancers are diagnosed at end stages, and unfortunately, the standard therapeutic strategies available for the treatment of affected women [including chemotherapy, radiotherapy and surgery] are not safe and effective enough. Moreover, the unwanted side-effects lowering the patients' life quality is another problem for these therapies. Therefore, researchers should search for better alternative/complementary treatments. The involvement of autophagy in the pathogenesis of various cancers has been demonstrated. Recently, a novel crosstalk between microRNAs, small non-coding RNAs with important regulatory functions, and autophagy machinery has been highlighted. In this review, we indicate the importance of this interaction for targeted therapy in the treatment of cancers including gynecological cancers, with a focus on underlying mechanisms.

What About the Others? Clinical Management of Gynecologic Cancer Risk in Patients With Moderate-Risk Hereditary Cancer Genes ( ATM , BRIP1 , RAD51C , RAD51D , and PALB2 ).

Hereditary cancer syndromes associated with gynecologic malignancies account for up to 18% of all cases of ovarian, uterine, and cervical cancers, and identification of these syndromes has implications for cancer screening and risk reduction techniques in affected patients. The associated cancer risks with moderate-penetrance genes are rapidly evolving and present variable risks for the provider counseling the patient. In this review, we detail the cancer risk and management of patients with germline PV in the moderate-risk hereditary cancer genes ATM , BRIP1 , RAD51C , RAD51D , and PALB2 .

Differential Receipt of Genetic Services Among Patients With Gynecologic Cancer and Their Relatives: A Review of Challenges to Health Equity.

Up to 14% of endometrial cancers and 23% of epithelial ovarian cancers are associated with genetic predispositions. Referral for genetic testing and counseling can significantly impact a patient's oncologic outcomes. However, significant disparities in genetic referral and testing exist within medically underserved and minority populations in the United States. These disparities in care and access to care are multifactorial, often involving patient-level, health care-level, and system-level factors. In this review, we focus on disparities in genetic testing among patients with ovarian and uterine cancer, and the missed opportunities for primary cancer prevention among their relatives.

Germline Variants of Uncertain Significance in Gynecologic Oncology Patients.

Germline and somatic genetic/genomic testing are commonly ordered for gynecologic oncology patients. Genetic tests can inform disease etiology, prognosis, treatment decisions, and risk to the patient's relatives. Variants of uncertain significance (VUSs) are frequently encountered and have a more nuanced interpretation than straightforward pathogenic or benign variant classifications. Clinical care providers should be familiar with why and how VUSs are reported, their clinical significance, variant reclassification practices, and patient perceptions of VUSs.

A comprehensive review on the role of PIWI-interacting RNA (piRNA) in gynecological cancers.

Gynecological cancers are currently a major public health concern due to increase in incidence and mortality globally. PIWI-interacting RNA (piRNA) are small non-coding RNA consisting of 24-32 nucleotides that plays regulatory role by interacting with piwi family of protein. Recent studies have revealed that piRNAs are expressed in various kinds of human tissues and influences key signalling pathways at transcriptional and post transcriptional levels. Studies have also that suggested piRNA and PIWI proteins display frequently altered expression in several cancers. Recent research has indicated that abnormal expression of piRNA may play a significant role in development and progression of gynecological cancers. Clinical studies suggested that, abnormally expressed piRNAs may serve as diagnostic and prognostic marker, and as potential therapeutic targets in these cancers. In the present review article, we discussed the emerging role of piRNA and their utility as diagnostic and prognostic marker in gynecological cancers.

The risk of endocrine interventions in carriers of a genetic predisposition for breast and gynecologic cancers: recommendations of the German Consortium for Hereditary Breast and Ovarian Cancer.

PURPOSE: To support doctors in counselling women with genetic predisposition for breast or gynecologic cancers on endocrine interventions. METHODS: Evidence on the safety of endocrine interventions for fertility treatment, contraception, hormone replacement therapy after risk-reducing salpingo-oophorectomy (RRSO) or treatment of symptoms during peri- and postmenopause was analysed for carriers of probably pathogenic and pathogenic variants in BRCA1 or BRCA2 (BRCA1/2-pV), in other breast and ovarian cancer genes and the Lynch Syndrome. Cancer risks were compared with data on risks for the general population. RESULTS: Data on risk modulation of endocrine interventions in women with genetic predisposition is limited. Ovarian hyperstimulation for fertility treatment may be performed. Oral contraceptives should not be used to reduce ovarian cancer risk in BRCA1/2-pV carriers. Premenopausal BRCA1/2-pV carriers and carriers of pV in Lynch Syndrome genes should be offered hormone replacement therapy (HRT) after RRSO, to prevent diseases caused by estrogen deficiency. CONCLUSION: Effect direction and strength of risk modulation by endocrine interventions is similar to the general population. Participation of individuals at risk in prospective registries is recommended.

Human papillomavirus disease in GATA2 deficiency: a genetic predisposition to HPV-associated female anogenital malignancy.

Objective: Patients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males. Methods: A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student's t-test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations. Results: Of 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males. Conclusion: Females with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

Unveiling Commonalities: Exploring Shared Characteristics in Clear-Cell Carcinomas of the Gynecologic Tract.

Clear-cell carcinomas (CCC) arising from the gynecologic tract (including from the ovary, endometrium, cervix, vulva, or vagina) represent rare but clinically significant entities with intriguing overlapping characteristics. Epidemiologically, CCCs exhibit a predilection for women of Asian ethnicity and are often associated with a previous or synchronous diagnosis of endometriosis. Pathologically, despite originating from different primary organs, CCCs of the gynecologic tract show similar morphologic and immunophenotypic features on traditional histopathology, such as the expression of napsin A and hepatocyte nuclear factor 1ß on IHC, without the expression of Wilms tumor 1. Well-described molecular characteristics of these cancers include recurrent mutations in genes such as ARID1A, PIK3CA, and/or PTEN, although significant variations exist across the different anatomic sites. Therapeutically, optimal management remains challenging due to the relative rarity of CCCs and limited subtype-specific clinical trials. Surgery remains the cornerstone of treatment, often complemented by systemic chemotherapy. However, promising drugs targeting angiogenesis or the immune microenvironment have emerged in recent years, leading to clinical successes, and are likely to reshape the therapeutic landscape of gynecologic CCC. This review summarizes the commonalities and disparities in terms of epidemiology, pathology, molecular features, and therapeutic approach, among CCCs of different anatomic origin, offering a foundation for further research and dedicated therapeutic interventions for these malignancies.

Stanniocalcin Protein Expression in Female Reproductive Organs: Literature Review and Public Cancer Database Analysis.

Stanniocalcin (STC) 1 and 2 serve as antihyperglycemic polypeptide hormones with critical roles in regulating calcium and phosphate homeostasis. They additionally function as paracrine and/or autocrine factors involved in numerous physiological processes, including female reproduction. STC1 and STC2 contribute to the pathophysiology of several diseases, including female infertility- and pregnancy-associated conditions, and even tumorigenesis of reproductive organs. This comprehensive review highlights the dynamic expression patterns and potential dysregulation of STC1 and STC2, restricted to female fertility, and infertility- and pregnancy-associated diseases and conditions, such as endometriosis, polycystic ovary syndrome (PCOS), abnormal uterine bleeding, uterine polyps, and pregnancy complications, like impaired decidualization, preeclampsia, and preterm labor. Furthermore, the review elucidates the role of dysregulated STC in the progression of cancers of the reproductive system, including endometrial, cervical, and ovarian cancers. Additionally, the review evaluates the expression patterns and prognostic significance of STC in gynecological cancers by utilizing existing public datasets from The Cancer Genome Atlas to help decipher the multifaceted roles of these pleiotropic hormones in disease progression. Understanding the intricate mechanisms by which STC proteins influence all these reviewed conditions could lead to the development of targeted diagnostic and therapeutic strategies in the context of female reproductive health and oncology.

Body Mass Index and Risk of Female Reproductive System Tumors Subtypes: A Meta-Analysis Using Mendelian Randomization.

Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577-1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216-1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.

Association between gynecologic cancer and Alzheimer's disease: a bidirectional mendelian randomization study.

BACKGROUND: Alzheimer's disease (AD) manifests with a higher rate of occurrence in women. Previous epidemiological studies have suggested a potential association between AD and gynecological cancers, but the causal relationship between them remains unclear. This study aims to explore the causal link between 12 types of gynecological cancers and AD using a bidirectional Mendelian randomization (MR) approach. METHODS: We obtained genetic correlation tools for AD using data from the most extensive genome-wide association study. Genetic correlation data for 12 types of gynecological cancers were also sourced from the Finnish Biobank. These cancers include breast cancer (BC), cervical adenocarcinoma (CA), cervical squamous cell carcinoma (CSCC), cervical cancer (CC), endometrial cancer (EC), ovarian endometrioid carcinoma (OEC), ovarian cancer (OC), ovarian serous carcinoma (OSC), breast carcinoma in situ (BCIS), cervical carcinoma in situ (CCIS), endometrial carcinoma in situ (ECIS), and vulvar carcinoma in situ (VCIS). We used the inverse-variance weighted (IVW) model for causal analysis and conducted horizontal pleiotropy tests, heterogeneity tests, MR-PRESSO tests, and leave-one-out analyses to ensure the robustness of our results. We also applied replication analysis and meta-analysis to further validate our experimental results. RESULTS: The study found that EC (P_IVW =0.037, OR [95% CI] = 1.032 [1.002, 1.064]) and CCIS (P_IVW = 0.046, OR [95% CI] = 1.032 [1.011, 1.064]) increase the risk of AD, whereas OC was negatively correlated with AD (P_IVW = 0.016, OR [95% CI] = 0.974[0.954, 0.995]). In reverse MR analysis, AD increased the risk of CC (P_IVW = 0.039, OR [95% CI] = 1.395 [1.017, 1.914]) and VCIS (P_IVW = 0.041, OR [95% CI] = 1.761 [1.027, 2.021]), but was negatively correlated with OEC (P_IVW = 0.034, OR [95% CI] = 0.634 [0.417, 0.966]). Sensitivity analysis results demonstrated robustness. These findings were further substantiated through replication and meta-analyses. CONCLUSIONS: Our MR study supports a causal relationship between AD and gynecological cancers. This encourages further research into the incidence of gynecological cancers in female Alzheimer's patients and the active prevention of AD.

Association between cholelithiasis, cholecystectomy, and risk of breast and gynecological cancers: Evidence from meta-analysis and Mendelian randomization study.

BACKGROUND: Observational studies have shown that cholelithiasis and cholecystectomy are associated with the risk of breast cancer (BC) and gynecological cancers, but whether these relationships are causal has not been established and remains controversial. METHODS: Our study began with a meta-analysis that synthesized data from prior observational studies to examine the association between cholelithiasis, cholecystectomy, and the risk of BC and gynecological cancers. Subsequently, a two-sample Mendelian randomization (MR) analysis was conducted utilizing genetic variant data to investigate the potential causal relationship between cholelithiasis, cholecystectomy, and the aforementioned cancers. RESULTS: The results of the meta-analysis demonstrated a significant association between cholecystectomy and the risk of BC (risk ratio [RR] = 1.04, 95% confidence interval [CI]: 1.01-1.06, p = 0.002) and endometrial cancer (EC) (RR = 1.26, 95% CI: 1.02-1.56, p = 0.031). Conversely, no significant association was observed between cholelithiasis and the risk of BC, EC, and ovarian cancer. The MR analysis revealed no discernible causal connection between cholelithiasis and overall BC (p = 0.053), as well as BC subtypes (including estrogen receptor-positive/negative). Similarly, there was no causal effect of cholecystectomy on BC risk (p = 0.399) and its subtypes. Furthermore, no causal associations were identified between cholelithiasis, cholecystectomy, and the risk of gynecological cancers (ovarian, endometrial, and cervical cancer [CC]) (all p > 0.05). CONCLUSION: This study does not support a causal link between cholelithiasis and cholecystectomy and an increased risk of female cancers such as breast, endometrial, ovarian, and CC.

Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers.

The PI3K signaling pathway plays an essential role in cancer cell proliferation and survival. PI3K pathway inhibitors are now FDA-approved as a single agent treatment or in combination for solid tumors such as renal cell carcinoma or breast cancer. However, despite the high prevalence of PI3K pathway alterations in gynecological cancers and promising preclinical activity in endometrial and ovarian cancer models, PI3K pathway inhibitors showed limited clinical activity in gynecological cancers. In this review, we provide an overview on resistance mechanisms against PI3K pathway inhibitors that limit their use in gynecological malignancies, including genetic alterations that reactivate the PI3K pathway such as PIK3CA mutations and PTEN loss, compensatory signaling pathway activation, and feedback loops causing the reactivation of the PI3K signaling pathway. We also discuss the successes and limitations of recent clinical trials aiming to address such resistance mechanisms through combination therapies.

Patients with gynecological malignancies are similar to other IVF patients without cancer for clinical and molecular reproductive parameters and DNA damage response pattern.

This study intended to investigate if gynecological cancers compromise ovarian function and reduce the success of assisted reproduction techniques (ART). No clinical and molecular data together is available on this issue for gynecological or other organ cancers. Steroidogenic pathways and DNA damage response characteristics of the granulosa cells retrieved from the 39 gynecological cancer patients were analyzed together with their clinical ART characteristics in comparison to 31 control ART patients. Patients with gynecological malignancies were similar to the control IVF patients for the number of mature oocytes retrieved, fertilization rates and embryo development competency. Molecular analyses of the granulosa cells retrieved from these cancer patients did not detect any perturbations in gonadotropin receptor expression and response, sex steroid production, cholesterol utilization/storage and, DNA damage response pattern in comparison to control IVF patients without cancer. This study provides the first reassuring clinical and molecular combined data set that the presence of gynecological malignancy does not appear to have any detrimental effect on clinical IVF cycle characteristics and ovarian functioning at molecular level.

The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers.

Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.