Increase In Risk Of Ovarian Cancer Research Articles

Causal relationship between thyroid dysfunction and ovarian cancer: a two-sample Mendelian randomization study

PurposeObservational studies and clinical validation have suggested a link between thyroid dysfunction and an elevated ovarian cancer (OC) risk. However, whether this association indicates a cause-and-effect relationship remains uncertain. We aimed to investigate the plausible causal impact of thyroid dysfunction on OC through a Mendelian randomization (MR) study.MethodsGenome-wide association study (GWAS) data for thyrotropin (TSH), free thyroxine (FT4), hypothyroidism, and hyperthyroidism were obtained as exposures and those for OC (N = 199,741) were selected as outcomes. Inverse variance-weighted method was used as the main estimation method. A series of sensitivity analyses, including Cochran’s Q test, MR-Egger intercept analysis, forest plot scatter plot, and leave-one-out test, was conducted to assess the robustness of the estimates.ResultsGenetic prediction of hyperthyroidism was associated with a potential increase in OC risk (odds ratio = 1.094, 95% confidence interval: 1.029–1.164, p = 0.004). However, no evidence of causal effects of hypothyroidism, TSH, and FT4 on OC or reverse causality was detected. Sensitivity analyses demonstrated consistent and reliable results, with no significant estimates of heterogeneity or pleiotropy.ConclusionsThis study employed MR to establish a correlation between hyperthyroidism and OC risk. By genetically predicting OC risk in patients with hyperthyroidism, our research suggests new insights for early prevention and intervention of OC.

The Association of Kidney Function and Inflammatory Biomarkers with Epithelial Ovarian Cancer Risk.

One of the mechanisms of ovarian tumorigenesis is through inflammation. Kidney dysfunction is associated with increased inflammation; thus, we assessed its relationship with ovarian cancer risk. In prospectively collected samples, we evaluated the association of kidney function markers and C-reactive protein (CRP) with ovarian cancer risk in the UK Biobank. We used multivariable-adjusted Cox proportional hazards models to evaluate quartiles of serum and urine markers with ovarian cancer risk overall and by histology. We assessed effect modification by CRP (≤3.0, >3.0 mg/L). Among 232,908 women (1,110 ovarian cancer cases diagnosed from 2006-2020), we observed no association between estimated glomerular filtration rate and ovarian cancer risk (Q4 vs. Q1: HR, 1.00; 95% confidence intervals, 0.83-1.22). Potassium was associated with endometrioid (Q4 vs. Q1: 0.33, 0.11-0.98) and clear cell (4.74, 1.39-16.16) tumors. Poor kidney function was associated with a nonsignificant increase in ovarian cancer risk among women with CRP>3.0 mg/L (e.g., uric acid Q4 vs. Q1; 1.23, 0.81-1.86), but not CRP≤3.0 mg/L (0.83, 0.66-1.05). Other associations did not vary across CRP categories. Kidney function was not clearly associated with ovarian cancer risk. Larger studies are needed to evaluate possible histology specific associations. Given the suggestive trend for increased ovarian cancer risk in women with poor kidney function and high CRP, future work is needed, particularly in populations with a high prevalence of inflammatory conditions. This study provided the first evaluation of markers of kidney function in relation to ovarian cancer risk.

Abstract P5-03-16: Changes in preferences for ovarian cancer prevention strategies during the COVID-19 pandemic: Results of a discrete choice experiment

Abstract Background: The COVID-19 pandemic influenced patient health care decisions, but there is little information about the pandemic’s impact on decisions about cancer risk reduction. This includes women at elevated risk of breast or ovarian cancer considering risk-reducing salpingo-oophorectomy (RRSO), risk-reducing salpingectomy (RRS), or other preventive measures. During the pandemic patients needed to balance their concerns about cancer risk reduction with their risks associated with elective health procedures, a risk which changed as vaccines became available. Methods: To address the impact of the COVID-19 pandemic on cancer prevention decision making, we recruited N=396 pre-menopausal women with a personal history of breast cancer or familial history suggestive of increased breast and/or ovarian cancer risk between 4/2019 and 3/2022. We conducted a discrete choice experiment in which patients were asked to choose between two scenarios that specified type of surgery (RRSO, RRS vs. non-surgical surveillance), age of menopause (natural versus immediate), quality of menopausal symptoms (mild, moderate, severe), and risk of ovarian cancer, heart disease, or osteoporosis. Risk of ovarian cancer for the scenarios provided varied in discrete intervals from 0% to 40%. We examined temporal trends during the pandemic using interactions with time coinciding approximately with the beginning of pandemic, peak vaccination period, and the Omicron wave. Results: We identified significant temporal interactions on a woman’s prevention decisions. In 2019, women at higher risk of ovarian cancer were more likely to choose prevention scenarios that favored lower ovarian cancer risk (odds ratio [OR] = 0.48; 95% CI = 0.37, 0.69 per 10% increase in ovarian cancer risk difference). This association decreased through the pre-vaccine period of 2020 by OR=2.61/month (95% CI = 1.21, 5.65). By June 2020, the effect of a 10% increase in ovarian cancer risk on intervention choice had attenuated substantially (OR=0.84, 95% CI 0.67, 1.00). By January 2022, the effect strengthened (OR= 0.69, 95% CI .49, .88), but had not reached pre-pandemic levels. Before 3/2020, natural age of menopause (versus immediate) had a strong impact on the choice of a scenario (OR=3.56, 95% CI 1.65-7.65). At the beginning of the pandemic, the effect was reduced by 0.47/month (95% CI 0.22-0.99). The rate of attenuation slowed over time, such that the effect of having a natural age of menopause on choice was OR= 1.56 (95% CI 0.65, 2.46) by January 2022. Tests for temporal interactions were statistically significant for both ovarian cancer risk and age of menopause. Conclusions: Our results suggest that over the course of the pandemic, women seemed more accepting of higher risks of ovarian cancer and immediate (post treatment) menopause when considering preventive options. There was an inverse U shape curve of the effect of ovarian cancer risk on choices over time (Figure A), but the strength of the relationship had not reached pre-pandemic levels by January 2022. This may reflect patient tolerance for side effects as the pandemic evolved. These results suggest that factors such as ovarian cancer risk and delay of menopause influenced personal prevention choices, but that these choices were influenced by events related to events that hallmarked the COVID-19 pandemic. Citation Format: Brian Egleston, Mary Daly, Kaitlyn Lew, Lisa Bealin, Alexander Husband, Jill Stopfer, Pawel Przybysz, Olga Tchuvatkina, Yu-Ning Wong, Judy Garber, Timothy Rebbeck. Changes in preferences for ovarian cancer prevention strategies during the COVID-19 pandemic: Results of a discrete choice experiment. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-16.

P-785 Assisted reproduction techniques and the risk of ovarian tumors

Abstract Study question Are fertility treatments associated with increased risk of subsequent development of ovarian tumors? Summary answer Results from recent studies have been primarily reassuring. However, further investigation is needed to determine whether fertility drug use increases the risk of ovarian tumors. What is known already In the last decades, the number of fertility treatments is rising worldwide due to postponing childbearing to a later age. The increasing exposure to fertility drugs has brought probable long term sequelae into focus, notably correlation with gynaecological malignancies. Two theories on the association between fertility drugs and ovarian cancer have been proposed, the “incessant ovulation” and the “elevated gonadotropin levels” theory. Use of assisted reproduction techniques (ART) is highly associated with many factors that are known to affect ovarian cancer risk such as parity. Study design, size, duration Summary of relevant clinical literature and review of all research studies that address the possible relation of assisted reproductive treatments with ovarian tumors. Participants/materials, setting, methods Published literature in PubMed, Medline and Google Scholar databases from 2011 to 2021 was screened using the following keywords: assisted reproductive techniques, in vitro fertilization, fertility drugs, ovarian cancer, and borderline ovarian tumors. Articles that were written in non- Latin alphabet were excluded for translational reasons. At least two review authors independently evaluated articles for eligibility. Main results and the role of chance Sixteen cohort and three case-control studies were selected. The majority of included studies reported no increase in ovarian cancer risk among subfertile women treated with ART, compared to either general population or subfertile non-treated women. In eight cohort and one case control studies, the type of fertility drug was clearly reported, including clomiphene citrate, gonadotropins, GnRH (gonadotropin releasing hormone) analogues, alone or in mixed protocols, while in the rest, the type of drug was not specified. Some studies showed a trend for a causative role of increasing dosage or number of IVF (in vitro fertilization) cycles, though statistically insignificant. Based on existing data, genetically vulnerable BRCA mutation carriers should not be excluded from use of ART, although extensive information of the potential association of ovarian stimulating drugs with ovarian tumors should be provided. Data on the association of fertility drug use with borderline ovarian tumors were contradictory. All included studies adjusted or matched for one or more possible confounding factors, such as age, parity and oral contraceptive use. Stratification by cause of infertility, showed an increased risk of ovarian cancer in treated women, with female factor infertility, which was more prominent in case of endometriosis. Limitations, reasons for caution High clinical and methodological heterogeneity of the included studies, with adjustment for varying confounding factors, relatively short follow–up periods and small samples sizes were noticed. Wider implications of the findings Ovarian cancer is the deadliest among all gynaecological malignancies. Considering the increasing use of ART worldwide, further clarification of the association between the two is crucial. For this reason larger, prospective studies are needed with sufficient follow-up exceeding 20years so that treated women will reach the ovarian cancer age range. Trial registration number not applicable

PCN194 Comparing Complex Machine Learning Models to Predict Likelihood of Ovarian Cancer Using Medicare Claims DATA

Ovarian cancer (OC) is difficult to detect and largely goes undiagnosed until late stages. Incidence of OC increases with age, and nearly half of women are diagnosed at age 65 or greater. This study aims to compare several models for predicting OC. The goal is to identify healthcare utilization patterns that are associated with an increased OC risk that may allow for intervention and reduce time to diagnosis. Using a de-identified claims database from 01/2017-05/2020, Medicare Advantage enrollees with OC were identified: 2+ claims with ICD-10 C56.x between 30 and 365 days apart. Patients were required to have continuous enrollment (CE) for ≥30 months prior to first OC claim and be between 66 to 85 years old at time of diagnosis. A control cohort was selected from women with equivalent age and CE criteria. We compared five algorithms in predicting likelihood of OC: LASSO logistic regression, decision tree, random forest, XGBoost, and CatBoost. A total of 876 women met study criteria for the OC cohort and 1,667 met study criteria for the control cohort. Random forest (sensitivity 0.96, specificity 0.88, precision 0.75) and XGBoost (sensitivity 0.87, specificity 0.92, precision 0.85) were the best performing models. Length of continuous enrollment, age, and pharmacy utilization in the two years prior had the highest feature importance for both models. Ambulatory utilization and total payer costs were also identified as important features in random forest and XGBoost respectively. Random forest and XGBoost performed well at predicting OC in a higher-risk Medicare Advantage population and may allow development of targeted interventions using claims data for early OC screening in women with higher healthcare utilization. Future iterations will explore implications of model sensitivity and specificity; minimum enrollment criteria will be assessed, and analysis will be extended to investigate model performance in a younger commercial population.

Attitudes towards risk-reducing early salpingectomy with delayed oophorectomy for ovarian cancer prevention: a cohort study.

To determine risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) acceptability and effect of surgical prevention on menopausal sequelae/satisfaction/regret in women at increased ovarian cancer (OC) risk. Multicentre, cohort, questionnaire study (IRSCTN:12310993). United Kingdom (UK). UK women without OC ≥18 years, at increased OC risk, with/without previous RRSO, ascertained through specialist familial cancer/genetic clinics and BRCA support groups. Participants completed a 39-item questionnaire. Baseline characteristics were described using descriptive statistics. Logistic/linear regression models analysed the impact of variables on RRESDO acceptability and health outcomes. RRESDO acceptability, menopausal sequelae, satisfaction/regret. In all, 346 of 683 participants underwent risk-reducing salpingo-oophorectomy (RRSO). Of premenopausal women who had not undergone RRSO, 69.1% (181/262) found it acceptable to participate in a research study offering RRESDO. Premenopausal women concerned about sexual dysfunction were more likely to find RRESDO acceptable (odds ratio [OR]=2.9, 95% CI1.2-7.7, P=0.025). Women experiencing sexual dysfunction after premenopausal RRSO were more likely to find RRESDO acceptable in retrospect (OR=5.3, 95% CI 1.2-27.5, P<0.031). In all, 88.8% (143/161) premenopausal and 95.2% (80/84) postmenopausal women who underwent RRSO, respectively, were satisfied with their decision, whereas 9.4% (15/160) premenopausal and 1.2% (1/81) postmenopausal women who underwent RRSO regretted their decision. HRT uptake in premenopausal individuals without breast cancer (BC) was 74.1% (80/108). HRT use did not significantly affect satisfaction/regret levels but did reduce symptoms of vaginal dryness (OR=0.4, 95% CI 0.2-0.9, P=0.025). Data show high RRESDO acceptability, particularly in women concerned about sexual dysfunction. Although RRSO satisfaction remains high, regret rates are much higher for premenopausal women than for postmenopausal women. HRT use following premenopausal RRSO does not increase satisfaction but does reduce vaginal dryness. RRESDO has high acceptability among premenopausal women at increased ovarian cancer risk, particularly those concerned about sexual dysfunction.

Use of fertility treatments in BRCA1/2 mutation carriers and risk for ovarian and breast cancer: a systematic review

PurposeMutations in the genes BRCA1 and BRCA2 represent a significant risk factor for ovarian and breast cancer. With increasing number and success rates, fertility protection and treatment are gaining importance also for BRCA1/2 mutation carriers. However, the effect on primary cancer risk and risk for recurrence remains unclear. This review analyses the published data on fertility treatment and risk of ovarian and breast cancer in BRCA1/2 mutation carriers.MethodsIn this review, we included all relevant articles published in English from 1995 to 2018. Literature was identified through a search on PubMed and Cochrane Library.ResultsWe identified one retrospective cohort and one case–control study regarding the association of fertility treatments and ovarian cancer risk in BRCA mutation carriers. The studies show no increase in ovarian cancer risk. Furthermore, one case–control study on the association between fertility treatment and breast cancer risk in BRCA mutation carriers and one prospective cohort study on the long-term safety of medication used for fertility preservation in women with a history of breast cancer were identified. One of the studies shows a possible adverse effect for gonadotropin-containing medication.ConclusionPossible increases in cancer risk associated with fertility treatments in BRCA1/2 mutation carriers cannot be excluded at this time. Based on the existing studies, BRCA1/2 mutation carriers should not be generally excluded from fertility treatments. However, they have to be informed about limited data and possible increases in cancer risk.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility.

This is an updated version of the original Cochrane Review published in the Cochrane Library in 2013 (Issue 8) on the risk of ovarian cancer in women using infertility drugs when compared to the general population or to infertile women not treated. The link between fertility drugs and ovarian cancer remains controversial. To evaluate the risk of invasive ovarian cancer and borderline ovarian tumours in women treated with ovarian stimulating drugs for subfertility. The original review included published and unpublished observational studies from 1990 to February 2013. For this update, we extended the searches from February 2013 to November 2018; we evaluated the quality of the included studies and judged the certainty of evidence by using the GRADE approach. We have reported the results in a Summary of findings table to present effect sizes across all outcome types. In the original review and in this update, we searched for randomised controlled trials (RCTs) and non-randomised studies and case series including more than 30 participants. At least two review authors independently conducted eligibility and 'Risk of bias' assessments and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We conducted no meta-analyses due to expected methodological and clinical heterogeneity. We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women.Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low.For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low.However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables. Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.

Parity-Dependent Hemosiderin and Lipofuscin Accumulation in the Reproductively Aged Mouse Ovary.

The progressive decline of the ovarian follicle pool leads to reproductive ageing. The latter is accompanied by age-related disorders, including various types of cancer. In fact, the highest rates of ovarian cancer (OC) occur at postmenopause while OC risk is significantly modulated by parity records during previous fertile life. We approached the age-parity relationship in the C57BL/6 mouse model and herein describe the presence of nonheme iron (hemosiderin) and deposits of the “age pigment” lipofuscin in reproductively aged mouse ovaries by applying conventional histochemical methods and autofluorescence. In addition, the 8-OHdG adduct was evaluated in ovarian genomic DNA. Both hemosiderin and lipofuscin were significantly higher in virgin compared to multiparous ovaries. The same pattern was observed for 8-OHdG. We conclude that nulliparity induces a long-term accumulation of iron and lipofuscin with concomitant oxidative damage to DNA in the mouse ovary. Since lipofuscin is a widely accepted senescence marker and given the recently postulated role of lipofuscin-associated iron as a source of reactive oxygen species (ROS) in senescent cells, these findings suggest a possible pathogenic mechanism by which nulliparity contributes to an increased OC risk in the postmenopausal ovary.

Ovarian cancer variant rs2072590 is associated with HOXD1 and HOXD3 gene expression.

Ovarian cancer (OC) is a common cancer in women and the leading cause of deaths from gynaecological malignancies in the world. In addition to the candidate gene approach to identify OC susceptibility genes, the genome-wide association study (GWAS) methods have reported new variants that are associated with OC risk. The minor allele of rs2072590 at 2q31 was associated with an increased OC risk, and was primarily significant for serous subtype. The OC risk-associated SNP rs2072590 lies in non-coding DNA downstream of HOXD3 and upstream of HOXD1, and it tags SNPs in the HOXD3 3′ UTR. We think that the non-coding rs2072590 variant may contribute to OC susceptibility by regulating the gene expression of HOXD1 and HOXD3. In order to investigate this association, we performed a bioinformatics analysis by a functional annotation of rs2072590 variant using RegulomeDB (version 1.1), HaploReg (version 4.1), and PhenoScanner (version 1.1). Using HaploReg, we identified 19 genetic variants tagged by rs2072590 variant with with r2 >= 0.8. Using RegulomeDB, we identified that three genetic variants are likely to affect TF binding + any motif + DNase Footprint + DNase peak. Other genetic variants are likely to affect TF binding + DNase peak. Using PhenoScanner (version 1.1), we identified that these 19 genetic variants could significantly regulate the expression of nearby genes, especially the HOXD1 and HOXD3 in human ovary tissue.

Introduction: Management of endometriosis: moving toward a problem-oriented and patient-centered approach

Endometriosis is a protean disease, and its manifestations, associated clinical problems, and possible treatments are numerous. Deep endometriosis that infiltrates multiple pelvic organs should be considered the most severe endometriotic form that poses the most difficult therapeutic uncertainties in both infertility and pelvic pain symptoms limiting quality of life. The available evidence demonstrates that endometriosis is not only a gynecologic disorder but, contrary to previous belief, its impact extends into pregnancy, delivery, and the post-partum period. The old clinical tenet that pregnancy is a cure for endometriosis may be revealed as fallacious. Safe and effective modalities to reduce the risk of the recurrence of symptoms and lesions after conservative surgery for endometriosis are now available. These treatment options should be offered post-operatively to women not immediately seeking conception. Endometriosis is associated with a moderate increase in ovarian cancer risk. However, as there are no definitive demonstrations that endometriosis constitutes per se a pre-neoplastic condition, it seems currently unwise to set-up a screening program to detect undiagnosed endometriosis in asymptomatic women. Endometriosis is not a cancer; therefore a paradigm shift from treatment of lesions to treatment of symptoms is warranted. Management should be shaped on the main clinical problem, taking into consideration a woman's preferences and priorities. Quantitative information should be provided to describe the potential benefits, potential harms, and costs of each treatment alternative. Counseling should be complete and transparent, and the duty of the caring gynecologist is to inform the woman on the pros and cons of each option and support her in the shared decision-making process. The physician should be able to explain in detail all the available treatments, and not only those that the physician prefers or is able to offer.

Expression of adiponectin and its receptors is altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines.

Recent evidence suggests that higher body mass index is associated with a modest increase in ovarian cancer risk. Reduced serum levels of adiponectin are correlated with obesity and increased cancer risk. The objectives of the present study are to determine if expressions of adiponectin and its receptors, AdipoR1 and AdipoR2, are altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines and to determine if plasma adiponectin levels are altered in the chicken model of ovarian cancer. Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations in ovaries and chicken ovarian cancer (COVCAR) cell lines were determined by quantitative real-time polymerase chain reaction analysis. Existence of adiponectin isoforms in the ovaries and COVCAR cells was identified by nondenaturing gel electrophoresis. Adiponectin, AdipoR1, and AdipoR2 protein amounts were determined by Western blot analysis. Plasma total adiponectin levels were determined by an enzyme immunoassay. Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations were significantly lower in cancerous ovaries and COVCAR cell lines compared with normal ovaries and normal ovarian surface epithelial (NOSE) cells, respectively. Adiponectin in ovary and COVCAR cell lines appeared as a heavy-molecular-weight isoform that is greater than 720-kd mass. In addition, a lower-molecular-weight adiponectin isoform was found in COVCAR cells but not in NOSE cells. Adiponectin and AdipoR1 protein concentrations were not different in COVCAR cell lines compared with NOSE cells. However, AdipoR2 protein concentrations were significantly higher in cancerous ovaries but lower in COVCAR cell lines compared with normal ovaries and NOSE cells, respectively. Plasma adiponectin concentrations were not different in chickens that had ovarian carcinoma compared with control animals. Expression of adiponectin in ovarian tumors and in metastatic ovarian tumor cells is likely to affect cellular metabolism and proliferation through activating AdipoR1 and/or AdipoR2. Plasma adiponectin levels may not be predictive of advanced stages of ovarian tumor in the chicken model.

Partner and Localizer of BRCA-2 (PALB-2) Mutation Analysis Is Rapidly Being Adopted into Clinical Practice.

To the Editor, Breast-Cancer Risk in Families with Mutations in PALB2: A.C. Antoniou, S. Casadei, T. Heikkinen, et al. N Engl J Med. 2014;371:497-506. In a study published in N Engl J Med. August 2014, researchers from 14 centers in eight countries investigated information from 362 family members from 154 families who had an abnormal partner and localizer of BRCA2 (PALB2) gene, but did not have an abnormal BRCA1 or BRCA2 gene. Their aim was to demonstrate the importance of loss-of-function mutations in PALB2 as a cause of hereditary breast cancer. The study included 311 women with an abnormal PALB2 gene; 229 of these women had been diagnosed with breast cancer and 51 men with an abnormal PALB2 gene; seven of whom had been diagnosed with breast cancer. The researchers compared the breast cancer risk of the study population to the general population. They found out that overall, women with an abnormal PALB2 gene had a risk of breast cancer that was 9.47 times higher than average. Women with an abnormal PALB2 gene had a 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. The average lifetime risk of breast cancer is about 12%. This increase in risk linked to an abnormal PALB2 gene was dependent on the women’s age and family history. They have demonstrated that the relative risk of breast cancer among PALB2 mutation carriers increased significantly as birth cohort became more recent (P<0.001). In women with an abnormal PALB2 gene, breast cancer risk was eight to nine times higher than average in women aged 20 to 39, six to eight times higher than average in women aged 40 to 60, and five times higher than average in women older than 60 years of age. By the age of 70, women with an abnormal PALB2 gene with no family history of breast cancer had a 33% risk of developing breast cancer whereas women with two or more first-degree relatives with breast cancer at 50 years of age had a 58% risk of developing the disease. The authors concluded that based on their estimates, breast cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. The researchers also reported that this level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2. A Genetic counselor’s perspective Partner and localizer of BRCA2 (PALB) is a gene whose protein facilitates the function of BRCA2 and interacts with BRCA1 to aid in repairing double strand and interstrand cross-link DNA damage. Biallelic PALB2 mutations cause Fanconi Anemia complement group N (FANCN) and monoallellic mutations in the PALB2 gene are associated with increased breast and pancreas cancer risks (1). PALB2 mutations may account for as much as 3% of familial breast cancer risk (2). A recent study of 362 members from PALB2 mutation positive families found that the risk for breast cancer in female mutation carriers ranged between 33% to 58% by age 70, with the higher risks relating to those women with a family history of early onset (<50) breast cancer in 2 first degree family members (3). The study also identified an 8 fold increase in male breast cancer risk and a 2 fold increase in ovarian cancer risk, both of which need to be confirmed in additional studies due a lack of statistical significance. These data suggest that female PALB2 mutation carriers may have breast cancer risks that are similar to those conferred by mutations in the BRCA2 gene. These findings suggest that women who carry PALB2 gene mutations may warrant similar breast cancer screening and prevention strategies as those offered to BRCA2 mutation carriers. PALB2 mutation analysis is available and is rapidly being adopted into clinical practice. As the data continues to accumulate it is likely that PALB2 mutation analysis will become a standard part of genetic testing in the realm of hereditary breast cancer predisposition. Whether testing will be done in addition to BRCA1/2 or as part of a larger breast cancer gene panel remains to be determined. In addition, more data will provide evidence to support the development of specific management guidelines to aid in the care of these at risk patients.

A prospective study of gynecological cancer risk in relation to adiposity factors: cumulative incidence and association with plasma adipokine levels.

BackgroundAssociations of obesity and obesity-related metabolic factors (adiposity factors) with uterine corpus cancer (UCC) and ovarian cancer (OVC) risk have been described. Still, a cause-effect relationship and the underlying mediators remain unclear, particularly for low-incidence populations. We aimed to prospectively determine whether adiposity factors could predict the development of UCC and OVC in Taiwanese women. To explore the biological mediators linking adiposity factors to cancer risk, we examined the association of two adipokines, leptin and adiponectin, with the gynecological cancers.MethodsTotally, 11,258 women, aged 30–65, were recruited into the Community-Based Cancer Screening Program (CBCSP) study during 1991–1993, and were followed for UCC and OVC cases until December 31, 2011. Cox proportional hazard models were used to estimate hazard ratios (HRs). Adiposity factors and risk covariates were assessed at recruitment. Newly-developed cancer cases were determined from data in the government’s National Cancer Registry and Death Certification System. For adipokienes study, a nested case-control study was conducted within the cohort. Baseline plasma samples of 40 incident gynecological cancer cases and 240 age-menopause-matched controls were assayed for adipokines levels.FindingsThere were 38 and 30 incident cases of UCC and OVC, respectively, diagnosed during a median 19.9 years of follow-up. Multivariate analysis showed that alcohol intake (HR = 16.00, 95% = 4.83–53.00), high triglyceride levels (HR = 2.58, 95% = 1.28–5.17), and years of endogenous estrogen exposure per 5-year increment (HR = 1.91, 95% = 1.08–3.38) were associated with increased UCC risk. High body mass index (BMI≥27 kg/m2, HR = 2.90, 95% = 1.30–6.46) was associated with increased OVC risk. Analysis further showed an independent effect of adipokines on UCC and OVC risk after adjustment of the risk covariates.ConclusionWe provided evidence that alcohol intake, high triglyceride levels and long endogenous estrogen exposure increase UCC risk, whereas obesity positively predicts OVC risk. Circulating adipokines may mediate the link of adiposity factors to gynecological cancer risk.

The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

Correlation between genetic polymorphisms within IL-1B and TLR4 genes and cancer risk in a Russian population: a case-control study

In the last decade, a growing interest has been devoted to the evaluation of the impact of single nucleotide polymorphisms (SNP) on cancer risk. According to the results of multiple studies, among the genes that have a considerable influence on cancer risk are those encoding pattern recognition receptors, cytokines, and antioxidant defense enzymes. Nonetheless, the effect of numerous SNPs within these genes on cancer risk has been scarcely investigated. A case-control study of 401 cases and 300 sex- and age-matched controls was performed in order to explore the role of IL1B_1473G/C (rs1143623), SOD1_7958A/G (rs4998557), TLR4_1196C/T (rs4986791), IL10_1082A/G (rs1800896), IL17A_197G/A (rs2275913), and TLR4_896A/G (rs4986790) polymorphisms in the susceptibility to colorectal cancer (n = 244), gastric carcinoma (n = 72), and ovarian cancer (n = 85). The analysis revealed a significant relationship between the presence of heterozygous genotypes for IL1B_1473G/C and TLR4_896A/G polymorphisms and higher risk of rectal cancer (codominant model, OR = 1.67; 95% CI, 1.06-2.63; p = 0.048 and OR = 2.25; 95% CI, 1.26-4.02; p = 0.014, respectively). In addition, the variant G/G genotype of the IL10_1082A/G SNP was associated with a 2.5-fold increase in ovarian cancer risk with a borderline significance (codominant model, OR = 2.45; 95% CI, 1.14-5.25; p = 0.069). Similarly, the carriers of the C/T genotype for the TLR4_1196C/T polymorphism were more susceptible to rectal cancer with a borderline significance (codominant model, OR = 1.42; 95% CI, 0.80-2.51 p = 0.06). No statistically significant associations were found when stratifying the sample by subgroups of age, sex, and clinicopathological characteristics. Finally, we observed six combinations of haplotypes for the examined SNPs, each of which either profoundly increased or decreased cancer risk. The results from our study provided evidence that IL1B_1473G/C and TLR4_896A/G SNPs are implicated in rectal cancer development in a Russian population. Further research should be addressed to clarify the role of the abovementioned polymorphisms in cancer etiology.

Mutations in BRIP1 confer high risk of ovarian cancer

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.

Inference From a Multiplicative Model of Joint Genetic Effects for Ovarian Cancer Risk

Inference From a Multiplicative Model of Joint Genetic Effects for Ovarian Cancer Risk

Awareness of ovarian cancer risk factors, beliefs and attitudes towards screening: baseline survey of 21 715 women participating in the UK Collaborative Trial of Ovarian Cancer Screening

Background:Women's awareness of ovarian cancer (OC) risks, their attitudes towards and beliefs about screening, together with misunderstandings or gaps in knowledge, may influence screening uptake.Methods:In total, 21 715 post-menopausal women completed questionnaires before randomisation into the UK Collaborative Trial of Ovarian Cancer Screening.Results:In all, 42.3% correctly identified their lifetime risk of OC; 87.1% knew that a family history of OC increased risk, but only 26.7% appreciated the association with a family history of breast cancer. Although 38.2% acknowledged increased risk post-menopause, only 8.8% were aware that OC diagnoses are highest in women over 65 years. Few (13.7%) recognised the association between pregnancy and reduced OC risk or protective effects of breastfeeding (6.2%). There were common misconceptions; 37.2% thought that an abnormal cervical smear and 26.4% that oral contraception increased the likelihood of OC. Although 84.4% recognised that most ovarian masses are benign, 20.2% thought having had a benign cyst increased OC risk. Most (99.4%) believed that a high uptake of OC screening would reduce mortality and (96.2%) that screen-detected cancers would have an improved prognosis.Conclusions:The results show a need for improved public understanding about OC risks and provide important information for GPs and health educationalists about initiatives needed for future awareness, prevention and screening programmes.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

Low–moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in ∼1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted Pdominant=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case–control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80–0.99) and remained statistically significant (Pdominant=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (Pglobal=0.034) and a haplotype in BRAF that had a protective effect (Pglobal=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.