Onset Of Ovarian Cancer Research Articles

Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma

Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction.We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026).TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.

Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients.

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored. To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes. In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis. In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

The deregulation of arachidonic acid metabolism in ovarian cancer.

Arachidonic acid (AA) is a crucial polyunsaturated fatty acid in the human body, metabolized through the pathways of COX, LOX, and cytochrome P450 oxidase to generate various metabolites. Recent studies have indicated that AA and its metabolites play significant regulatory roles in the onset and progression of ovarian cancer. This article examines the recent research advancements on the correlation between AA metabolites and ovarian cancer, both domestically and internationally, suggesting their potential use as biological markers for early diagnosis, targeted therapy, and prognosis monitoring.

Exploring the causal role of multiple metabolites on ovarian cancer: a two sample Mendelian randomization study

BackgroundThe mechanisms and risk factors underlying ovarian cancer (OC) remain under investigation, making the identification of new prognostic biomarkers and improved predictive factors critically important. Recently, circulating metabolites have shown potential in predicting survival outcomes and may be associated with the pathogenesis of OC. However, research into their genetic determinants is limited, and there are some inadequacies in understanding the distinct subtypes of OC. In this context, we conducted a Mendelian randomization study aiming to provide evidence for the relationship between genetically determined metabolites (GDMs) and the risk of OC and its subtypes.MethodsIn this study, we consolidated genetic statistical data of GDMs with OC and its subtypes through a genome-wide association study (GWAS) and conducted a two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method served as the primary approach, with MR-Egger and weighted median methods employed for cross-validation to determine whether a causal relationship exists between the metabolites and OC risk. Moreover, a range of sensitivity analyses were conducted to validate the robustness of the results. MR-Egger intercept, and Cochran’s Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. False discovery rate (FDR) correction was applied to validate the findings. We also conducted a reverse MR analysis to validate whether the observed blood metabolite levels were influenced by OC risk. Additionally, metabolic pathway analysis was carried out using the MetaboAnalyst 5.0 software.ResultsIn MR analysis, we discovered 18 suggestive causal associations involving 14 known metabolites, 8 metabolites as potential risk factors, and 6 as potential cancer risk reducers. In addition, three significant pathways, "caffeine metabolism," "arginine biosynthesis," and "citrate cycle (TCA cycle)" were associated with the development of mucinous ovarian cancer (MOC). The pathways "caffeine metabolism" and "alpha-linolenic acid metabolism" were associated with the onset of endometrioid ovarian cancer (OCED).ConclusionsOur MR analysis revealed both protective and risk-associated metabolites, providing insights into the potential causal relationships between GDMs and the metabolic pathways related to OC and its subtypes. The metabolites that drive OC could be potential candidates for biomarkers.

Ferroptosis: mechanism, immunotherapy and role in ovarian cancer.

Ovarian cancer is currently the second most common malignant tumor among gynecological cancers worldwide, primarily due to challenges in early diagnosis, high recurrence rates, and resistance to existing treatments. Current therapeutic options are inadequate for addressing the needs of ovarian cancer patients. Ferroptosis, a novel form of regulated cell death with demonstrated tumor-suppressive properties, has gained increasing attention in ovarian malignancy research. A growing body of evidence suggests that ferroptosis plays a significant role in the onset, progression, and incidence of ovarian cancer. Additionally, it has been found that immunotherapy, an emerging frontier in tumor treatment, synergizes with ferroptosis in the context of ovarian cancer. Consequently, ferroptosis is likely to become a critical target in the treatment of ovarian cancer.

Endometriosis and epithelial ovarian cancer: a two-sample Mendelian randomization analysis

Endometriosis, a prevalent condition, has long been recognized as a chronic and debilitating ailment affecting an estimated 1790 million women worldwide. Observational studies have established a correlation between endometriosis and ovarian cancer. Thus, we endeavored to employ Two-Sample Mendelian Randomization, utilizing summary statistics from a Genome-Wide Association Study of endometriosis and epithelial ovarian cancer, with genetic markers serving as proxies for epithelial ovarian cancer. The analysis revealed a significant correlation between these entities, with an odds ratio (OR) of 1.23 (95% CI 1.11–1.36). Upon histotype-specific examination, robust evidence emerged for an association of endometriosis with the risk of endometrioid carcinoma (OR 1.49, 95% CI 1.24–1.81), clear cell carcinoma (OR 2.56, 95% CI 1.75–3.73), and low malignant potential tumors (OR 1.28, 95% CI 1.08–1.53). These findings provide a theoretical framework for prospective investigations aimed at enhancing the potential therapeutic efficacy of managing endometriosis in averting the onset and progression of ovarian cancer.

Prevalence and Landscape of Pathogenic or Likely Pathogenic Germline Variants and Their Association With Somatic Phenotype in Unselected Chinese Patients With Gynecologic Cancers

Understanding germline and somatic status in patients with gynecologic cancers could improve risk assessment and guide therapeutic decision-making. To evaluate the prevalence and landscape of germline pathogenic or likely pathogenic (P/LP) variants and explore whether these variants are associated with somatic phenotypes and cancer risk in unselected patients with gynecologic cancers. This cross-sectional study retrospectively enrolled unselected patients in China with a gynecologic cancer, including ovarian, cervical, and endometrial, who underwent tumor-normal sequencing using a 520-gene panel from October 1, 2017, through May 31, 2021. Germline variants in gynecologic cancers. The P/LP germline variant rates in 62 cancer predisposition genes were assessed using descriptive statistics. The associations of P/LP variant status with age, somatic profiles, and cancer risk were also investigated using the Fisher exact test or Student t test. A total of 1610 women (median [IQR] age, 54 [47-62] years; 1201 [74.6%] with stage III-IV disease) were included (945 with ovarian cancer, 307 with endometrial cancer, and 358 with cervical cancer). The prevalence of patients with P/LP variants was 20.5% (194 of 945) for ovarian cancer, 13.4% (41 of 307) for endometrial cancer, and 6.4% (23 of 358) for cervical cancer; 95.1% of the germline findings (n = 252) were potentially actionable, mainly in homologous recombination repair (HRR) and mismatch repair genes. Chinese patients with endometrial cancer had a higher rate of P/LP variants than a White population from The Cancer Genome Atlas (42 of 307 [13.7%] vs 24 of 367 [6.5%]; P = .003). In endometrial and cervical cancers, the prevalence of P/LP variants was 12.7% (30 of 237) and 4.8% (13 of 270), respectively, in patients diagnosed at age 45 years or older and increased to 25.0% (9 of 36; P = .09) and 12.0% (10 of 83; P = .04), respectively, for those with an onset age of less than 45 years. Mismatch repair P/LP variants were associated with a younger age at onset for ovarian cancer (46 vs 54 years; P = .02) and endometrial cancer (48 vs 57 years; P < .001), while HRR P/LP variants were associated with a younger age at onset for cervical cancer (46 vs 52 years; P = .04). Carriers of HRR P/LP variants had more prevalent somatic TP53 variants and less common somatic variants in oncogenic driver genes vs noncarriers. BRCA1/2 P/LP variants were also associated with moderate risks for endometrial and cervical cancer. This study delineates the landscape of germline P/LP variants in Chinese women with gynecologic cancers. The findings highlight the hereditary factor in cervical cancer that has long been neglected and suggest the importance of next-generation sequencing-based genetic testing with a large gene panel for gynecologic cancers.

The Clinical Significance of Genetic Variation in Ovarian Cancer.

Genetic variation is a well-known contributor to the onset and progression of cancer. The goal of this study is to provide a comprehensive examination of the nucleotide and chromosomal variation associated with the onset and progression of serous ovarian cancer. Using a variety of computational and statistical methods, we examine the exome sequence profiles of genetic variants present in the primary tumors of 432 ovarian cancer patient samples to compute: (1) the tumor mutational burden for all genes and (2) the chromosomal copy number alterations associated with the onset/progression of ovarian cancer. Tumor mutational burden is reduced in the late vs. early stages, with the highest levels being associated with loss-of-function mutations in DNA-repair genes. Nucleotide variation and copy number alterations associated with known cancer driver genes are selectively favored over ovarian cancer development. The results indicate that genetic variation is a significant contributor to the onset and progression of ovarian cancer. The measurement of the relative levels of genetic variation associated with individual ovarian cancer patient tumors may be a clinically valuable predictor of potential tumor aggressiveness and resistance to chemotherapy. Tumors found to be associated with high levels of genetic variation may help in the clinical identification of high-risk ovarian cancer patients who could benefit from more frequent monitoring.

The importance of the regularity of preventive examinations in the early diagnosis of ovarian cancer

Objective. To show the importance of regularity of preventive examinations in early diagnostics of ovarian cancer. Malignant ovarian tumors occupy the third place in the frequency of occurrence among the gynecological tumors after cancer of the uterine body and cervix but they leave them behind with regard to the mortality rate. Detection of the disease at late stages leads to only 17 % five-year survival rate in Europe and Russia.&#x0D; Materials and methods. A prospective study was conducted on the basis of the Gynecological Unit of Perm Regional Oncological Dispensary. It enclosed 50 patients aged 45 to 77 years, operated for ovarian cancer with various stages of the disease. The following methods were used: collection of complaints and anamnesis, study of outpatient cards and medical histories, assessment of morphological conclusions.&#x0D; Results. According to the anamnesis, all patients represented a risk group for ovarian cancer. The annual gynecological preventive examination was carried out in 40 % of patients, ultrasound examination of the pelvic organs was performed in 28 % of cases. The smallest group,10 % of patients, was a group of patients with stage I of the disease and asymptomatic course of pathology, who underwent preventive examinations and ultrasound in 100 % of cases. The largest number of patients had stage III 40 %, annual preventive examinations were carried out in 20 % of women of this group without ultrasound examination of the pelvic organs. In 64 % of cases, a late examination by a doctor was detected a year or more after the symptoms of the disease occurred. Patients with stages III and IV of the disease were postmenopausal, were unemployed and lived in rural areas.&#x0D; Conclusions. The absence of symptoms at an early stage of ovarian cancer and late onset of treatment with the complaints available actualizes the need for annual preventive gynecological examinations with mandatory ultrasound verification of the diagnosis to identify the disease in time.

Genetically Engineered Artificial Exosome-Constructed Hydrogel for Ovarian Cancer Therapy.

Owing to the insidious onset of ovarian cancer, most patients are in the advanced stage with extensive peritoneal metastasis when they are diagnosed. Treatment of peritoneal metastasis from advanced ovarian cancer remains a significant challenge. Inspired by the massive macrophages in the peritoneal environment, here, we reported an artificial exosome-based peritoneal-localized hydrogel to domesticate peritoneal macrophages as the therapeutic target for realizing potent ovarian cancer therapy, where artificial exosomes derived from genetically sialic-acid-binding Ig-like lectin 10 (Siglec-10)-engineered M1-type macrophages were chemically designed as gelator. Upon triggering immunogenicity with X-ray radiation, our hydrogel encapsulating efferocytosis inhibitor MRX-2843 enabled a cascade regulation to orchestrate polarization, efferocytosis, and phagocytosis of peritoneal macrophages for realizing robust phagocytosis of tumor cells and powerful antigen presentation, offering a potent approach for ovarian cancer therapy via bridging the innate effector function of macrophages with their adaptive immune response. Moreover, our hydrogel is also applicable for potent treatment of inherent CD24-overexpressed triple-negative breast cancer, providing an emerging therapeutic regimen for the most lethal malignancies in women.

The Role of NQO1 in Ovarian Cancer.

Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance onset. Several researchers reported that oxidative stress plays a key role in ovarian cancer occurrence, growth and development. The NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that, using NADH or NADPH as substrates to reduce quinones to hydroquinones, avoids the formation of the highly reactive semiquinones, then protecting cells against oxidative stress. In this review, we report evidence from the literature describing the effect of NQO1 on ovarian cancer onset and progression.

Abstract 6603: BRCA1 promoter methylation in sporadic breast cancer patients detected by liquid biopsy

Abstract Background: BRCA1 promoter methylation (PM) is an early initiating event in cancer, occurring in 3 to 65.2% of all breast tumors, and 30 to 65% of triple negative tumors. BRCA1 PM has been associated with defective homologous recombination repair (HRR), early onset of breast and ovarian cancer, and improved clinical response to adjuvant chemotherapy. Historically, there has been no diagnostic assay that comprehensively evaluates both BRCA1 PM and genomic alterations in cell-free circulating tumor DNA (ctDNA). Here, we describe the novel detection of BRCA1 PM and genomic alterations in a cohort of patients with breast cancer using GuardantINFINITY, a liquid biopsy assay interrogating 800+ genes and genome-wide methylation detection. Method: We assessed for BRCA1 PM in ctDNA from 274 patients with late-stage breast cancer. Genomic sequencing of 800+ genes and PM profiling of 398 genes was performed by GuardantINFINITY. The positive calling threshold for PM was established by comparing cell-free DNA derived from patients with cancer and cancer-free donors. The limit of detection (LoD) was determined through in silico and experimental titrations of ctDNA from clinical samples and cell lines with known gene PM into the plasma of cancer-free donors. Results: Among the 274 patients with advanced breast cancer, 8 (2.9%) had germline pathogenic mutations in BRCA1, BRCA2, or ATM. BRCA1 PM was detected in 11/274 (4.0%) patients at the predefined threshold of &amp;gt;99% specificity. BRCA1 PM detection in this cohort was 8.9% (8/90) when excluding samples with low tumor shedding (&amp;lt;1% epigenomic tumor fraction in cfDNA). Among the 11 patients with BRCA1 PM detected in ctDNA, one had a co-occurring somatic BRCA1 nonsense variant (p.S361*); none of the remaining patients with BRCA1 PM had another HRR-related mutation detected in cfDNA. Among patients without BRCA1 PM detected, pathogenic somatic alterations were detected in BRCA2, ATM, and CHEK2 in 25 (9.4%) patients. In silico simulations using clinical samples with BRCA1 PM indicated an LoD of 0.0408%. BRCA1 PM was not detected in 3210 individual and mixed cancer-free clinical samples, indicating a high specificity for BRCA1 PM calls. Conclusion: GuardantINFINITY, a plasma-based diagnostic assay, detected both BRCA1 PM and genomic alterations in this unspecified advanced breast cancer cohort. The BRCA1 PM detection rates of 4.0-8.9% are consistent with values previously reported in the literature. As BRCA1 PM has important prognostic and therapeutic implications for the management of breast (as well as ovarian) cancers, additional studies are warranted to further describe the PM patterns across breast cancer subtypes and how these patterns both influence and are influenced by disease evolution and therapeutic response. Liquid biopsy thus serves as a suitable method to noninvasively identify and monitor changes in both genomics and epigenomics. Citation Format: Jennifer Yen, Sai Chen, Colby Jenkins, Brooke Overstreet, Yu Fu, Jun Zhao, Tingting Jiang, Leylah Drusbosky, Stephen Pettitt, Michael Dorschner, Lauren Lawrence, Han-Yu Chuang, Andrew Tutt. BRCA1 promoter methylation in sporadic breast cancer patients detected by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6603.

Abstract P031: Glycerolipid metabolism is a key early-detection biomarker for spontaneous ovarian cancer onset

Abstract Ovarian cancer (OVC) is the fifth leading cause of cancer death in women and the most lethal gynecological cancer due to its inability to be diagnosed early. OVC is very treatable in its early stages, however, it is usually not identified until it’s at a later stage and survivability is low. Early symptoms of OVC such as abdominal pain, bloating, and changes in diet or bathroom habits are nonspecific and thus OVC is a challenge to diagnose early. Identification of early-detection blood biomarker(s) will allow for quicker and more informed treatment decisions and have a direct bearing on enhancing the survival rate. To this end, we use the chicken model of OVC to model spontaneous human OVC initiation and progression. Egg-laying hens develop OVC in much the same way as humans do; spontaneously and without known genetic predisposition. The layer hen has a fully sequenced genome with ~60% gene correspondence and ~99% gene similarity to humans. This combined with reproductive similarities to humans such as repetitive ovulation, gene function, and ovarian cellular makeup are what have validated the hen as an accurate model for OVC study. Moreover, disease presentation and disease grade are highly similar across the two species. Monthly blood draws were performed on specific-pathogen-free (SPF) hens during their entire lifecycle from reproductive prime to spontaneous development of OVC. Blood plasma from young, high laying hens (exhibiting repetitive ovulation, similar to the reproductive prime in women) and older, low-laying hens (those with slowing ovulation, similar to menopausal women) were analyzed for ~550 different metabolites using mass spectrometry. Glycerolipid metabolism was identified as a key early indicator of ovarian health. OVC requires lipid-rich nutrients for growth and spread, as is seen with metastasis often occurring to the omentum, a fat-rich organ. Our results also revealed that steroid biosynthesis was another major pathway in differentiating the cohorts. Upregulated fatty acid metabolism and regulation are associated with increased risk of cancer development as they have roles in cell support, structure, and signaling. Uncovering these early-stage diagnostic and prognostic biomarkers will have a direct bearing on enhancing patient survival rates and improve quality of life. Citation Format: Kathryn Ellwood, Ashley Taylor, Aditya Dutta. Glycerolipid metabolism is a key early-detection biomarker for spontaneous ovarian cancer onset. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P031.

Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients

ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer.MethodsThis was a multicenter, international,...

Do autoimmune diseases influence the onset and progression of ovarian cancer? A systematic review and meta-analysis

ObjectiveOvarian cancer remains the fifth leading cause of cancer-related deaths in women. The immune system influences the onset and progression of ovarian cancer. Therefore, we aimed to study the behavior...

Non-apoptotic cell death in ovarian cancer: Treatment, resistance and prognosis.

Ovarian cancer is mostly diagnosed at an advanced stage due to the absence of effective screening methods and specific symptoms. Repeated chemotherapy resistance and recurrence before PARPi are used as maintenance therapies, lead to low survival rates and poor prognosis. Apoptotic cell death plays a crucial role in ovarian cancer, which is proved by current researches. With the ongoing development of targeted therapy, non-apoptotic cell death has shown substantial potential in tumor prevention and treatment, including autophagy, ferroptosis, necroptosis, immunogenic cell death, pyroptosis, alkaliptosis, and other modes of cell death. We systematically reviewed the research progress on the role of non-apoptotic cell death in the onset, development, and outcome of ovarian cancer. This review provides a more theoretical basis for exploring therapeutic targets, reversing drug resistance in refractory ovarian cancer, and establishing risk prediction models that help realize the clinical transformation of vital drugs.

Genetic, clinic and histopathologic characterization of BRCA-associated hereditary breast and ovarian cancer in southwestern Finland

We have analyzed the histopathological, clinical, and genetic characteristics in hereditary breast and ovarian cancer patients of counselled families from 1996 up to today in the southwestern Finland population. In this study we analyzed the incidence of different BRCA1 and BRCA2 pathogenic variants (PV). 1211 families were evaluated, and the families were classified as 38 BRCA1 families, 48 BRCA2 families, 689 non-BRCA families and 436 other counselled families (criteria for genetic testing was not met). In those families, the study consisted of 44 BRCA1 breast and/or ovarian cancer patients, 58 BRCA2 cancer patients, 602 non-BRCA patients and 328 other counselled patients. Breast cancer mean onset was 4.6 years earlier in BRCA1 carriers compared to BRCA2 (p = 0.07, a trend) and ovarian cancer onset almost 11 years earlier in BRCA1 families (p < 0.05). In BRCA families the onset of ovarian cancer was later than 40 years, and BRCA2-origin breast cancer was seen as late as 78 years. The BRCA PV (9%) increases the risk for same patient having both ovarian and breast cancer with a twofold risk when compared to non-BRCA group (4%) (95% CI p < 0.05). Triple-negativity in BRCA1 (42%) carriers is approximately 2.6 times vs more common than in BRCA2 carriers (16%) (p < 0.05). The risk ratio for bilateral breast cancer is approximately four times when compared BRCA2 (17%) and other counselled patients’ group (4%) (p < 0.05). 27% southwestern BRCA2-families have a unique PV, and correspondingly 39% of BRCA1-families. The results of this analysis allow improved prediction of cancer risk in high-risk hereditary breast and ovarian families in southwestern Finland and improve long term follow-up programs. According to the result it could be justified to have the discussion about prophylactic salpingo-oophorectomy by the age of 40 years. The possibility of late breast cancer onset in BRCA2 carriers supports the lifelong follow-up in BRCA carriers. Cancer onset is similar between BRCA2 carries and non-BRCA high-risk families. This study evaluated mutation profile of BRCA in southwestern Finland. In this study genotype–phenotype correlation was not found

Leptin Protein Expression and Promoter Methylation in Ovarian Cancer: A Strong Prognostic Value with Theranostic Promises.

Ovarian cancer (OC) is the deadliest among all gynecological cancers. Epidemiological studies showed that obesity might influence many cancers including OC. One of the key factors that may link obesity and OC is leptin (LEP), known as an adipokine with pleiotropic effects on body homeostasis. This study aims to investigate the expression pattern of LEP, assess the methylation profiles of LEP and their associations with clinicopathological features including survival outcomes of OC patients. The protein expression of LEP was evaluated in 208 samples using both tissue microarray and immunohistochemistry techniques. The methylation profiles of LEP were measured in 63 formalin-fixed, paraffin-embedded tumor tissues by quantitative polymerase chain reaction using a MethyLight assay. Our results showed a significant association of LEP protein overexpression with several clinicopathological variables, mainly tumor subtype, LVI, age of menarche, tumor size and stage (p < 0.04). Kaplan–Meier analysis (using low expression versus high expression as a discriminator) indicated that LEP protein overexpression is a powerful positive prognosticator of both OC recurrence (DFS) and disease-specific survival (DSS) in our OC cohort (log-rank p = 0.01 and p = 0.002, respectively). This implies that patients with high LEP expression profiles live longer with less recurrence rates. Methylation analysis results demonstrated a clear association between no/low LEP protein expression pattern (38%) and LEP promoter CpG island hypermethylation (43%). Results of this study suggest that LEP is a powerful prognosticator of OC recurrence and DSS. LEP expression in OC seems to be regulated by its promoter hypermethylation through gene partial/total silencing. Further multi-institutional studies using larger cohorts are required to demystify the intricate molecular functions of this leptin-driven effects in OC pathophysiology and to accurately assess its theranostic potential and validate its prognostic/predictive power in OC onset, progression towards more effective and personalized management of OC patients.

Endometriosis, hormonal therapy and oncological risks

Endometriosis is now considered as benign disease. However, a correlation was found between endometriosis and several types of cancer. Endometriomas are found in 17–44% of patients with endometriosis and can be frequent precursors of ovarian cancer (endometrioid and clear cell ovarian tumors are more common). This process can be realized through several mechanisms: predominance of certain cytokines, oxidative stress and local hyperestrogenia, genetic mutations including PTEN, PIK3CA, ARID1A, Wnt/β-catenin, microsatellite instability, Src and KRAS.There are no generally accepted approaches to non-invasive early diagnosis of ovarian cancer, especially in borderline tumors and early stages of malignancy. The lack of accurate screening programs for ovarian cancer emphasizes the importance of identifying high-risk, moderate-risk, and low-risk groups. Screening is not recommended in the general population in the low-risk group. Annual CA125 evaluation and transvaginal pelvic ultrasound with general and special gynecological examination are recommended in the moderate-risk group in postmenopause. Transvaginal ultrasound of the pelvic organs with CA125 evaluation is performed every 6 months in the high-risk group, starting from 30 years or 5–10 years before the youngest age of ovarian cancer onset in relatives. The main method of diagnosing tumors is expert ultrasound of the pelvic organs (simultaneously with transabdominal ultrasound). The main tumor markers are CA125 (single evaluation has low diagnostic value), risk malignancy index (RMI) and HE4.Clinical trials are going on and various methods of prevention, screening and treatment of these diseases are being developed. Probably, dienogest can help to solve the problem. Existing results of research are promising, but insufficient since they show both the positive effects of progestin therapy and minor cases of cancer detection during therapy that are not related to the use of progestins, but probably indicate unknown mechanisms of transformation in endometriosis.

Mismatch repair gene alteration subtypes impact age of onset of mismatch repair-deficient cancers.

10521 Background: This study investigated whether mismatch repair (MMR) gene alterations and alteration subtypes impacted age at onset of MMR-deficient cancers. Methods: A retrospective study of association of MMR-deficient alterations and age of onset of MMR-deficient lung, breast, prostate, bladder, colorectal, endometrial, and/or ovarian cancers was conducted by using cBIPORTAL dataset. Results: A total of 815 participants with MMR-deficient alterations were enrolled, 346 males and 469 females (median age 63 years; age range, 20-90 years). Males were diagnosed as colorectal and bladder cancer at later ages than females. When stratified by alteration type, individuals with MSH6 or PMS2 missense alterations had later ages of onset of colorectal cancer than those with no missense alterations. Participants with MSH2 AMP alterations were older at the diagnosis of endometrial cancer than those without MSH2 AMP alterations. Females with MLH1 missense alterations had later ages of onset of ovarian cancer than those with no missense alterations. Individuals with PMS2 AMP alterations were confirmed with lung cancer at later ages than those with no PMS2 AMP alterations. Carriers with MSH6or PMS2 missense alterations were older at the time of diagnosis of prostate cancer than those with no missense alterations. Conclusions: Gene alterations and subtype of alterations could stratify carriers with MMR-deficiency in bespoke surveillance. The mechanism of the association of MMR-deficient alterations and alteration subtypes and age at the diagnosis of MMR-deficient cancers needs to be further study.[Table: see text]