Risk Of Ovarian Cancer Research Articles

Fertility treatment and risk of ovarian cancer in a large nationwide cohort of infertile Danish women.

Whether fertility treatment increases the risk of ovarian cancer has been a concern for many decades, but previous research has yielded conflicting findings. We therefore investigated this association within a large population-based cohort study of infertile women aged 20-45 years and living in Denmark between 1995 and 2017, as identified in the Danish Infertility Cohort (n = 146,110). The study cohort was linked to nationwide registers to obtain information on fertility drug use, cancer diagnoses, covariates, emigration, and vital status was. Hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for ovarian cancer overall and for serous ovarian cancer were estimated using Cox proportional hazard models. During a median 10.3 years of follow-up, 114 women were diagnosed with ovarian cancer of which 65 had serous ovarian cancer. Our results showed that the rate of serous ovarian cancer (HR 1.92; 95% CI 1.16-3.17) was increased after every use of progesterone but the association was not affected by increased follow-up time since first use or with increased cumulative dose. We performed a secondary analysis adding less extensive data from 1971 through 1994 from the Danish Infertility Cohort. In this study cohort, 332 women developed ovarian cancer of which 192 had serous ovarian cancer. The overall results were similar, including the association between every use of progesterone and serous ovarian cancer (HR 2.05: 95% CI: 1.31-3.21). In conclusion, the novel finding that use of progesterone is associated with an increased rate of serous ovarian cancer warrants further investigation.

Breast cancer and ATM mutations: treatment implications.

Genetic testing for breast cancer predisposing genes has expanded beyond BRCA1 and BRCA2 and now includes panels of 20 or more genes. It is now recommended that all women diagnosed with breast cancer at age 65 or below be offered testing for an extended gene panel. The rationale for testing includes personalizing the management of breast cancer according to the mutation found. For BRCA1 and BRCA2 carriers, the finding of a mutation has clear implications for cancer management, but for other genes, such as ATM, the management implications are less clear. Women with an ATM mutation have a lifetime risk of breast cancer of approximately 25%, the majority of which are ER-positive. The risk of ovarian cancer is approximately 5%. It is not yet clear how the identification of an ATM mutation in a patient newly diagnosed with breast cancer should impact on her treatment and follow-up. At present, these women are treated in the same way as women without a mutation. It is important that large prospective studies be conducted looking at various treatment modalities in women with breast cancer and an ATM mutation in order to optimize outcomes.

Assessing the impact of contraceptive use on reproductive cancer risk among women of reproductive age—a systematic review

BackgroundContraceptives play a crucial role in women's reproductive health, their hormonal components may be linked to cancer risks, specifically breast, and gynecological cancers. Given the high usage rates of hormonal contraceptives, it is vital to systematically evaluate their potential impact on cancer outcomes, especially among women with a family history of gynecological cancers.ObjectivesThis study aims to evaluate the evidence on the association between modern contraceptive use and the risk of breast and reproductive cancers (ovarian, endometrial, and cervical cancer) among women of reproductive age, to inform healthcare providers, women, and program managers about cancer outcomes related to contraceptive use.MethodsA systematic review was conducted according to PRISMA guidelines. Searches were performed in databases such as CINAHL, OVID Medline, EMBASE, and more from inception to February 2022. Eligible studies included randomized controlled trials, cohort studies, and case-control studies that compared cancer outcomes between contraceptive users and non-users. Data extraction, quality assessment, and meta-analyses were conducted following predefined protocols. Subgroup and sensitivity analyses examined variations in contraceptive methods, doses, and duration.ResultsA total of 51 studies were included, comprising 2 RCTs and 49 observational studies. The review identified a significant reduction in ovarian and endometrial cancer incidence among contraceptive users. Hormonal contraceptive users had a 36% lower risk of ovarian cancer (RR 0.64, 95% CI 0.60–0.68), with specific reductions seen in combined oral contraceptive users (RR 0.62, 95% CI 0.57–0.68) and hormonal IUD users (RR 0.68, 95% CI 0.48–0.96). The rate ratio of cervical cancer was higher among non- users compared to hormonal contraceptive users when we pooled the results (1.28, 95% CI 1.21, 1.35). No significant association was found between contraceptive use and breast cancer risk among healthy women (RR 1.00, 95% CI 0.94–1.06). However, BRCA1/2 mutation carriers using oral contraceptives showed a heightened risk of breast cancer (HR 1.39, 95% CI 1.15–1.67).ConclusionThis systematic review highlights the protective effects of modern contraceptives against ovarian and endometrial cancers while identifying an increased risk of cervical. No significant breast cancer risk was found for healthy women, but BRCA1/2 mutation carriers faced increased risks. These findings underscore the need for personalized contraceptive counselling that considers cancer risk factors. Further research is needed to explore contraceptive impacts across different genetic profiles and dosing regimens.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, Prospero (CRD42022332647).

Ayurvedic Management of Osteoporosis W.S.R. to Asthikshaya- A Pilot Study

Osteoporosis is marked by a substantial decrease in bone mass and a deterioration of the microarchitecture of bone tissue, which increases the risk of fractures. This condition often goes unnoticed until a fracture occurs, which is why it is often referred to as a "silent disease". Asthikshaya is an Ayurvedic term that refers to the depletion, degeneration, or weakening of Asthi Dhatu (bone tissue). It occurs when there is an insufficient formation or nourishment of the Asthi Dhatu, leading to a decrease in bone density and strength. This condition can manifest as bone weakness, brittle nails and teeth, hair loss, joint pain, and a greater risk of fractures or bone-related disorders, such as osteoporosis. Worldwide, an osteoporotic fracture happens every three seconds, significantly impacting individuals and disrupting their lives. By the age of 50, the probability of sustaining a fracture is one in three for women and one in five for men. The incidence of hip fractures in women is greater than the combined risk of breast, ovarian, and uterine cancers, while for men, the risk of hip fractures exceeds that of prostate cancer. Alarmingly, about 50% of individuals who experience an initial osteoporotic fracture will suffer additional fractures, with the risk escalating with each subsequent incident. In the present clinical study, 15 clinically proven patients of Osteoporosis were treated with Asthiposhtika Vati to evaluate its therapeutic effectiveness. Ayurvedic parameters (Lakshanas) of Asthikshaya were used as subjective parameters to assess the effectiveness of the drug. Statistical analysis was conducted using the t-test, and the results were encouraging, indicating that Asthiposhtika Vati (Anubhoot yoga) is effective in managing osteoporosis, thereby exploring various aspects of this clinical condition.

Prevalence of BRCA1 and BRCA2 mutations in ovarian cancer patients from Yunnan Province in southwest China.

Carriers with germline breast cancer 1/2 gene mutations (BRCAm) are likely to develop ovarian cancer (OC). Therefore, identifying these mutations may enable individualized therapy for OC and preventive measures to reduce OC risk in BRCAm carrier families. Thus, we investigated the prevalence of BRCAm in OC patients from Yunnan Province in Southwest China. In total, 674 unselected OC patients were enrolled and tested for BRCAm via next-generation sequencing. Data on clinicopathological characteristics and personal/family history of cancer were collected. The prevalence rates of pathogenic/likely pathogenic BRCAm were 26.6% overall, 20.8% among BRCA1m carriers, 5.5% among BRCA2m carriers, and 0.3% among carriers of both BRCA1m and BRCA2m. The most common pathogenic mutation in the BRCA1 gene was c.5114T>C (n = 9). The number of BRCAm carriers was significantly greater among patients with serous cancer, a personal tumor history, a family history of hereditary breast and ovarian cancer (HBOC)-related tumors, and bilateral tumors. The most common pathogenic mutation in this cohort was c.5114T>C (n = 9) in BRCA1. The prevalence and spectrum of BRCAm in OC patients from Yunnan Province are different from those in other groups. BRCA status testing is advised for all OC patients, particularly those with a family history of HBOC.

Risk for second primary ovarian cancer: a large population based on Surveillance, Epidemiology, and End Results database.

This study aims to evaluate the likelihood of developing a second primary ovarian cancer (OC) considering factors including age, race, and the types of initial malignancies encountered. This study employed a retrospective cohort approach, compiling data on individuals diagnosed with OC from the Surveillance, Epidemiology, and End Results (SEER) program databases spanning the years 1975 to 2019. The analysis used standardized incidence ratios (SIR) with 95% confidence intervals (CI) to determine the likelihood of developing OC. The result was further refined by categorizing the data based on patient age, race background, first primary cancer types, the time elapsed since the second primary cancer diagnosis, and radiotherapy treatment. A total of 1,536,151 patients with second primary cancer being OC were included. The SIR of the second primary OC was observed to be elevated among patients between the ages of 18 to 64 years (SIR: 1.09, 95% CI: 1.06-1.13). In contrast, for patients who were 65 years of age or older, the SIR for a second primary OC was found to be relatively lower (SIR: 0.87, 95% CI: 0.83-0.91). A lowering, however not statistically significant, of the SIR of the second primary OC in patients with white race was presented. Within 2 months to 1-year diagnosis interval, the SIR of the second primary OC was highest (SIR: 1.48, 95% CI: 1.37-1.61). Liver, gallbladder, intrahepatic, and other bile ducts (SIR: 2.00, 95% CI: 1.38-2.81), and breast cancer (SIR: 1.20, 95% CI: 1.15-1.25) had higher SIRs of second primary OC. This study identifies age, ethnicity, the time span between the diagnoses, and the types of initial cancers as factors correlated with the occurrence of a second primary OC. Our findings suggest that targeted surveillance should be considered for high-risk groups.

Association between gut microbiota, plasma metabolites, and ovarian cancer: A Mendelian randomization study.

Numerous studies have demonstrated a correlation between alterations in gut microbiota (GM) and levels of body metabolites in ovarian cancer (OC). However, the specific causal relationships underlying these associations remain unclear. This study utilized summary statistics of GM from the MiBioGen consortium, along with an unprecedented dataset comprising 1091 blood metabolites and 309 metabolite ratios from the UK Biobank, in conjunction with OC data from the FinnGen Consortium R9 release. We conducted bidirectional Mendelian randomization (MR) analyses to investigate the causal relationships between GM and OC. Additionally, a two-step MR approach was employed to identify potential mediating metabolites. Our analysis revealed significant associations between 6 specific microbiota taxa and OC. Furthermore, we identified several plasma metabolites that act as mediators of the association between GM and OC. In the two-step MR analysis, we observed a negative correlation between 4-methoxyphenol sulfate and pregnenetriol disulfate levels with OC. The genus Lachnospiraceae UCG008 potentially increases the risk of OC by decreasing 4-methoxyphenol sulfate levels, while the genus Howardella may elevate the risk of OC by reducing pregnenetriol disulfate levels, with mediation proportions of 22.35% and 4.23%, respectively. Additionally, levels of dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2) were positively correlated with OC. The inhibitory effect of the genus Ruminococcus 1 on OC may be mediated through 1,2-dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2), with mediation proportions of 10.15% and 11.32%, respectively. Our findings highlight the complex relationship among GM, plasma metabolites, and OC. The identified associations and mediation effects offer valuable insights into potential therapeutic approaches targeting GM for the management of OC.

Carrier Frequency and Incidence of MUTYH-Associated Polyposis Based on Database Analysis in East Asians and Koreans.

MUTYH-associated polyposis is an autosomal recessive disorder associated with an increased lifetime risk of colorectal cancer and a moderately increased risk of ovarian, bladder, breast, and endometrial cancers. We analyzed the carrier frequency and estimated the incidence of MUTYH-associated polyposis in East Asian and Korean populations, for which limited data were previously available. We examined 125,748 exomes from the gnomAD database, including 9,197 East Asians, and additional data from 5,305 individuals in the Korean Variant Archive and 1,722 in the Korean Reference Genome Database. All MUTYH variants were interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines and the Sequence Variant Interpretation guidelines from ClinGen. The global carrier frequency of MUTYH-associated polyposis was 1.29%, with Europeans (non-Finnish) having the highest frequency of 1.86% and Ashkenazi Jews the lowest at 0.06%. East Asians and Koreans had a carrier frequency of 0.35% and 0.37% and an estimated incidence of 1 in 330,409 and 1 in 293,304 in Koreans, respectively, which were substantially lower than the global average of 1 in 24,160 and the European (non-Finnish) incidence of 1 in 11,520. This was the first study to investigate the frequency of carriers of MUTYH-associated polyposis in East Asians, including specific subgroups, utilizing gnomAD and a Korean genome database. Our data provide valuable reference information for future investigations of MUTYH-associated polyposis to understand the genetic diversity and specific variants associated with this condition in East Asian populations.

Pattern Anlysis of Risk-Reducing Strategies in Unaffected Korean BRCA1/2 Mutation Carriers

The lifetime risk of breast and ovarian cancer increases substantially for individuals with mutations in BRCA1/2. The evidence indicates that BRCA1/2 mutation carriers benefit from early cancer detection and prevention strategies. However, data on the patterns of risk-reducing interventions are lacking. This study investigated the patterns of surveillance and risk-reducing interventions among unaffected BRCA1/2 mutation carriers. A cohort of unaffected BRCA1/2 mutation carriers was identified from the Korean Hereditary Breast cAncer (KOHBRA) study database, and a telephone survey was conducted. The survey included questions on the incidence of new cancers, patterns of cancer (breast, ovarian, prostate, other) surveillance, chemoprevention, risk-reducing surgery, and reasons for participating in risk-reducing strategies. Between November 2016 and November 2020, 192 BRCA1/2 mutation carriers were contacted, of which 83 responded. After excluding 37 responders who refused to participate, 46 participants (15 males, 31 females) were included in the analysis. The mean ± SD follow-up time was 103 ± 17 months (median 107, range 68~154), and the mean ± SD age was 31 ± 8 years. Ten BRCA1/2 mutation carriers developed breast cancer, one developed ovarian cancer, and three developed other cancers. Six BRCA1/2 mutation carriers (19.4%) underwent annual breast cancer surveillance as recommended by guidelines, while none underwent ovarian or prostate cancer surveillance. Three carriers (9.7%) used chemoprevention for breast cancer. Risk-reducing salpingo-oophorectomy was performed on only one BRCA1/2 mutation carrier. The rates of breast/ovarian cancer surveillance, chemoprevention, and risk-reducing surgery were low among unaffected Korean BRCA1/2 mutation carriers. Given this cohort’s relatively high risk of developing breast cancer, strategies to encourage active participation in risk reduction are needed.

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

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. 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. 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). 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.

Physician variation in adopting prophylactic salpingectomy at the time of postpartum sterilization for ovarian cancer risk reduction

Physician variation in adopting prophylactic salpingectomy at the time of postpartum sterilization for ovarian cancer risk reduction

Optimization of docetaxel-loaded cholesterol nanostructured lipid carriers for improving cancer treatment using Taguchi experimental design

Today's diets boost breast, head, neck, ovarian, and lung cancer risk. This has prompted researchers to study active compounds against these slow killers. Docetaxel (DTX) loaded onto cholesterol nanostructured lipid carriers (NLCs) with elaidic acid appears promising. Carriers were made using solvent emulsification-diffusion. This study used Taguchi's experimental design and analysis with the L16 orthogonal array. The design was utilised to analyse NLC particle size and zeta potential data. These trials considered process factors like elaidic acid percentage (15–30 %), emulsifier concentration (1–4 %), agitation duration (2–8 min), and blending speed (800–1400 rpm). Controlled experimental design plays an important role in pharmaceutical research, as does the privilege of a comprehensive technique aimed to maximize the creation of NLCs loaded with DTX for cancer treatment. Blending speed had a substantial influence on particle size, as the lowest and maximum particle sizes were 170.54 and 190.90 nm. In the zeta potential research, values ranged from 5.88 to 30.72 mV. These data show how important blending speed is in determining particle size. This research supports the sustainable development goals of 3, 9, 12, and 17.

BRCA Mutation in Ovarian Cancer: Implications for Screening, Diagnosis, and Preventive Measures

Ovarian cancer is the most common gynaecological malignancy and the seventh most common malignancy in women. Inherited ovarian cancer is caused by mutations in certain genes, such as BRCA1 and BRCA2, as well as many minor genes. The pathology of ovarian cancer involves damage to the cell cycle mechanism secondary to mutations in BRCA1/2 protective genes. These mutations provide a meaningful marker for screening and diagnosing hereditary ovarian cancer. Classification of ovarian cancer is based on histology, depending on which layers of the ovary are affected. The authors conducted an electronic search using keywords and selected the included studies based on pre-established inclusion criteria. To avoid bias in the data extraction process, three reviewers extracted information independently. Risk assessment models provided by the National Comprehensive Cancer Network (NCCN) and American College of Obstetricians and Gynecologists (ACOG) are mostly used in clinical practice. The combination of serial serum cancer antigen-125 (CA-125) levels and transvaginal ultrasound is the only evidence-based screening approach available to patients at increased risk for ovarian cancer. Strong evidence has made salpingo-oophorectomy the gold standard for risk-reducing surgery. Bilateral salpingectomy, in contrast, is restricted to clinical trials currently. The protective effects of oral contraceptives have made them suitable agents for chemoprevention. Whilst the potential benefits of aspirin and certain other drugs have been investigated, further research is required to address the gap in data for them to be used in clinical practice for the purpose of ovarian cancer prevention.

Risk-stratified CA125 screening integrating CA125 trajectories, trajectory-specific progression and transvaginal ultrasound for ovarian cancer

BackgroundsCancer antigen 125 (CA125) is widely used for screening ovarian cancer (OC), yet its effectiveness remains debated. Potential factors may include ineffective cut-off value for CA125 in screening, as well as a lack of consideration for CA125 trajectories and trajectory-specific progression.MethodsBased on data from multiple rounds of CA125 tests and transvaginal ultrasound (TVU) examinations conducted on 28,456 women in the PLCO Trial, time-dependent receiver-operating-characteristic curves (ROCs) and area-under-the-curves (tdAUCs) analyses were employed to identify the optimal CA125 cut-off values for OC screening. Participants were categorized into four CA125 trajectories: stable negative CA125 (CA125SN), loss of positive CA125 (CA125LP), stable positive CA125 (CA125SP), and gain of positive CA125 (CA125GP). The associations between different CA125 trajectories, trajectory-specific progression indicators, and OC risk were explored. The effectiveness of risk-stratified CA125 screening, incorporating CA125 trajectories, trajectory-specific progression, and TVU, was evaluated using hazard ratio and 95% confidence intervals [HR (95%CIs)], with adjustments for potential confounders.ResultsAfter a median follow-up of 14.8 years for OC incidence and 23.8 years for OC mortality, 250 OC cases and 218 OC deaths were identified. The tdAUC for 10-year OC incidence with CA125 was 0.663, with an optimal cut-off value of 13.00 U/ml. Trajectory analyses showed that both CA125SP and CA125GP were significantly associated with increased risks of OC incidence [HRs (95%CIs): 2.00(1.47–2.73) and 3.06(2.25–4.16)] and mortality [HRs (95%CIs):1.58(1.13–2.21) and 2.60(1.87–3.62)] compared to CA125SN. Trajectory-specific progression analyses identified relative velocity as the optimal progression indicators for both CA125SP and CA125GP (tdAUCs: 0.712 and 0.767), with optimal cut-off values of 9% and 32% per year, respectively. Positive progression was associated with significantly increased risks of OC incidence [HRs (95%CI): 7.26(4.00-13.17) and 3.83(1.96–7.51) CA125GP and CA125SP] and mortality [HRs (95%CI): 8.03(4.15–15.56) and 6.04(2.78–13.14)] compared to negative progression. Optimized risk-stratified CA125 screening, which integrated CA125 trajectories, trajectory-specific progression, and TVU, reduced missed OC by 3.6% and improved accuracy compared to traditional screening methods.ConclusionsIncorporating CA125 trajectories and trajectory-specific progression into screening protocols enhances the identification of the population at high-risk of OC. An optimized screening strategy, which includes these factors along with TVU, is recommended to improve the effectiveness of OC screening.

A Rare Case of Triple-Negative Breast Cancer with RAD51D Gene Mutation

Background: The heterogeneity of breast cancer (BC) subtypes poses a significant challenge, with carcinogenesis involving multiple stages and genes, including proto-oncogenes, tumor suppressor genes, and DNA repair genes. Next-generation sequencing has expanded access to multigene panels, such as RAD51 paralogs, which increase the risk of ovarian cancer and possibly triple-negative (TN) BC. Case presentation: We present a rare case of a 45-year-old woman with TNBC and a RAD51D gene mutation. Mammography and breast ultrasonography revealed an irregular, 30 mm hypoechoic area and dystrophic calcifications in the right breast. Immunohistochemistry showed a lack of expression of ER, RP, HER-2, and P53, with 50% of neoplastic cell nuclei positive for Ki-67. Next-generation sequencing revealed a mutation in RAD51D and MUYTH genes. The patient underwent partial mastectomy, chemotherapy, and prophylactic mastectomy. Conclusion: Genetic analysis is crucial for identifying specific mutations contributing to TNBC development. Current preventive interventions primarily address BRCA1 and BRCA2 mutations, following established guidelines.

Causal relationship between amino acids and ovarian cancer in the European population: A bidirectional Mendelian randomization study and meta-analysis.

In recent years, an increasing number of observational studies have reported the impact of amino acids on ovarian cancer. However, Mendelian randomization studies have not yet been conducted to explore the causal relationship between them in the context of ovarian cancer. This study conducted Mendelian randomization (MR) analysis of 20 amino acids in relation to ovarian cancer data from 2 different sources within the European population, using a two-sample MR approach. The primary results from the inverse variance weighting analysis were then subjected to a meta-analysis, followed by multiple testing correction for the meta-analysis thresholds. Finally, reverse causality testing was performed on the positively associated amino acids and ovarian cancer. MR analyses were conducted for 20 amino acids with ovarian cancer data from both the Finngen R10 and Open genome-wide association study databases. The inverse variance weighted results from these 2 analyses were then combined through meta-analysis, with multiple corrections applied to the significance thresholds of the meta-analysis results. The findings showed that only cysteine had a significant association with ovarian cancer, with an (odds ratio) odds ratio value of 0.507 (95% confidence interval: 0.335-0.767, P = .025). The P-value of the combined MR and meta-analysis, after multiple testing correction, was 0.025, indicating statistical significance (P < .05). Additionally, cysteine did not show a reverse causal relationship with ovarian cancer in either data source. Cysteine is a protective factor for ovarian cancer, potentially reducing the risk of ovarian cancer and slowing the progression of the disease.

Establishment of a clinical cancer genetics program for breast cancer in a resource-limited country; challenges and opportunities.

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2, may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains.

Venous thromboembolism and ovarian cancer risk: a Mendelian randomized study

IntroductionA potential link between venous thromboembolism and the risk of ovarian cancer has been identified in clinical practice. However, it is unclear whether there is a causal relationship between the two. In this study, we applied a univariate two-sample Mendelian randomization method to explain the possible link between venous thromboembolism and ovarian cancer pathogenesis at the genetic level, and pointed out that lipid metabolism and ovarian cancer pathogenesis have innovative basic experimental directions.ObjectiveThis study explored the causal effect between a history of venous thromboembolism and the risk of ovarian cancer.MethodsGenome-Wide Association Study (GWAS) data of venous thromboembolism patients (n = 9176) of the same ethnicity were selected as study exposures, and GWAS data of ovarian cancer patients (n = 1218) of the same ethnicity were selected as study exposures. In this study, univariate two-sample Mendelian randomization analysis (UVMR) was performed separately using inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) to assess causal effects. In this study, Cochran’s Q test, MR-Egger regression intercept term, MR-PRESSO, and leave-one-out method were used for sensitivity analysis to assess the stability and reliability of the results.ResultsThe GWAS data screened in this study were all European ethnicity data. In this study, we found that genetically predicted history of venous thromboembolism was associated with an upward trend in ovarian cancer incidence, and the results of Weighted median, Simple mode, Weighted mode, and MR Egger showed a similar trend (OR = 1.0006, 95% CI: 1.00007–1.0013, p < 0.05). There was no heterogeneity of results (p = 0.18) and no horizontal pleiotropy (p = 0.77). The instrumental variables selected for venous thromboembolism in this study were all strong instrumental variables (F = 669.7). The results of the sensitivity analysis remained consistent.ConclusionThe results of this study indicate that patients with a history of venous thromboembolism are at increased risk of developing ovarian cancer and point to possible associations between lipid metabolism genes, such as CYP4V2, and the development of ovarian cancer, which provide interesting directions for further basic research.

Two founder variants account for over 90% of pathogenic BRCA alleles in theOrkney and Shetland Isles in Scotland.

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK populations. Here, we report a BRCA2 splice acceptor variant, c.517-2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as pathogenic. Exome sequence data from 2108 VIKING I participants with three or more Shetlandic grandparents was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is ~130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of Whalsay, Shetland, similar to our observations for the BRCA1 founder variant c.5207T>C from Westray, Orkney. In total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two drifted variants. We thus provide the scientific evidence of an opportunity for screening people of Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or Whalsay ancestry.

Exploring estrogen-related mechanisms in ovarian carcinogenesis: association between bone mineral density and ovarian cancer risk in a multivariable Mendelian randomization study.

Estrogen may play a role in epithelial ovarian cancer (EOC) carcinogenesis, with effects varying by EOC histotype. Measuring women's long-term exposure to estrogen is difficult, but bone mineral density (BMD) may be a reasonable proxy of longer-term exposure. We examined this relationship by assessing the association between genetic predisposition for higher BMD and risk of EOC by histotype. We used Mendelian randomization (MR) to assess associations between genetic markers for femoral neck and lumbar spine BMD and each EOC histotype. We used multivariable MR (MVMR) to adjust for probable pleiotropic traits, including body mass index, height, menarcheal age, menopausal age, smoking, alcohol intake, and vitamin D. Univariable analyses suggested greater BMD was associated with increased risk of endometrioid EOC (per standard deviation increase; lumbar spine OR = 1.21; 95% CI 0.93,1.57, femoral neck: OR = 1.25; 0.99,1.57), but sensitivity analyses indicated that pleiotropy was likely. Adjustment using MVMR reduced the magnitude of estimates slightly (lumbar spine: OR = 1.13; 95% CI 1.00,1.28, femoral neck: OR = 1.18; 1.03,1.36). Results for lumbar spine BMD and high-grade serous EOC were also suggestive of an association (univariable MR: OR = 1.16; 95% CI 1.03,1.30; MVMR: OR = 1.06; 0.99,1.14). Our study found associations between genetic predisposition to higher BMD, a proxy for long-term estrogen exposure, and risk of developing endometroid and high-grade serous EOC cancers. These findings add to existing evidence of the relationship between estrogen and increased risk of EOC for certain histotypes.