There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.
Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histological subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.
Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared to women in the lowest (95% CI 1.48-1.84). Analyses by histological subtype yielded risk differences across subtype for endometriosis (phet<0.001), parity (phet<0.01), and tubal ligation (phet=0.041).
The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of each risk factor's effect, which sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histological subtype is warranted.
Gene-environment interactions; ovarian cancer; epidemiology; histological subtype; pooled analysis
To evaluate the validity of self-reported hysterectomy against the gold standard of uterine visualisation using pelvic ultrasound.
Prospective cohort study.
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) based in 13 National Health Service (NHS) Trusts in England, Wales and Northern Ireland.
Between April 2001 and October 2005, 48 215 postmenopausal women aged 50–74 randomised to the ultrasound screening arm of UKCTOCS underwent the first (initial) scan on the trial.
At recruitment, the women completed a recruitment questionnaire (RQ) which included previous hysterectomy. The sonographer asked each woman regarding previous hysterectomy (interview format, IF) prior to the scan. At the scan, in addition to ovarian morphology, endometrial thickness (ET)/endometrial abnormality were captured if the uterus was visualised at the scan.
Self-reported hysterectomy at RQ or IF was compared to ultrasound data on ET/endometrial abnormality (as surrogate uterine visualisation markers) on the first (initial) scan.
Of 48 215 women, 3 had congenital uterine agenesis and 218 inconclusive results. The uterus was visualised in 39 121 women. 8871 self-reported hysterectomy at RQ, 8641 at IF and 8487 at both. The uterus was visualised in 39 123, 39 353 and 38 969 women not self-reporting hysterectomy at RQ, IF or both. Validity, sensitivity, specificity, positive predictive value and negative predictive value of using RQ alone, IF or both RQ/IF were 99.6%, 98.9%, 99.7%, 98.9% and 99.7%; 98.9%, 98.4%, 99.1%, 95.9% and 99.7%; 99.8%, 99.6%, 99.9%, 99.4% and 99.9%, respectively.
Self-reported hysterectomy is a highly accurate and valid source for studying long-term associations of hysterectomy with disease onset.
International Standard Randomised Controlled Trial Number (ISRCTN)—22488978
Gynaecology; Epidemiology; Oncology
To establish the performance characteristics of annual transvaginal ultrasound and serum CA125 screening for women at high risk of ovarian/fallopian tube cancer (OC/FTC) and to investigate the impact of delayed screening interval and surgical intervention.
Patients and Methods
Between May 6, 2002, and January 5, 2008, 3,563 women at an estimated ≥ 10% lifetime risk of OC/FTC were recruited and screened by 37 centers in the United Kingdom. Participants were observed prospectively by centers, questionnaire, and national cancer registries.
Sensitivity for detection of incident OC/FTC at 1 year after last annual screen was 81.3% (95% CI, 54.3% to 96.0%) if occult cancers were classified as false negatives and 87.5% (95% CI, 61.7% to 98.5%) if they were classified as true positives. Positive and negative predictive values of incident screening were 25.5% (95% CI, 14.3 to 40.0) and 99.9% (95% CI, 99.8 to 100) respectively. Four (30.8%) of 13 incident screen-detected OC/FTCs were stage I or II. Compared with women screened in the year before diagnosis, those not screened in the year before diagnosis were more likely to have ≥ stage IIIc disease (85.7% v 26.1%; P = .009). Screening interval was delayed by a median of 88 days before detection of incident OC/FTC. Median interval from detection screen to surgical intervention was 79 days in prevalent and incident OC/FTC.
These results in the high-risk population highlight the need for strict adherence to screening schedule. Screening more frequently than annually with prompt surgical intervention seems to offer a better chance of early-stage detection.
Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.
Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.
We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.
These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies.
These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.
To explore beliefs of Chinese American, immigrant women related to breast cancer and mammography.
Qualitative description with semi-structured focus groups.
Metropolitan Portland, Oregon.
Thirty eight foreign-born Chinese women, age 40 and older, in five focus groups.
Focus group discussions in Chinese were audio taped, transcribed, and translated into English. Using a process of directed content analysis, group transcripts were coded for themes based on the discussion guide.
Three main themes emerged from the analysis: knowledge and beliefs; support, communication, and educational needs; and access to care. Subthemes included beliefs such as barriers and facilitators to screening and perceptions about personal breast cancer risk. Several women were profoundly affected by the negative breast cancer-related experiences of relatives and friends. Some common myths remain about causes and treatment of breast cancer.
Although Chinese American immigrant women share beliefs with other minority women in the United States, some culturally-related barriers such as alienation due to cultural reasons for not sharing diagnosis with anyone and beliefs about the efficacy of Eastern versus Western medicine may affect adherence to screening and treatment. Facilitators included being told to get the test and getting screened for the sake of the family, while erroneous information about the cause of breast cancer such as diet and stress remained. Primary care providers such as advanced practice nurses should take into account culturally driven motivations and barriers to mammography adherence among Chinese American immigrant women. Provider-client interactions should involve more discussion about women’s breast cancer risks and screening harms and benefits. Such awareness could open a dialogue around breast cancer that is culturally sensitive and non-threatening to the patient. Information may need to be tailored to women individually or targeted to sub-ethnic groups rather than using generic messages for all Asian immigrant women.
Breast cancer; Chinese Immigrant women; Health beliefs; Focus groups
Recent genome-wide association studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate or low penetrance variants exist among the subset of SNPs not well tagged by the genotyping arrays used in the previous studies which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by the less dense arrays. However our study lacked power to make clear statements on the existence of hitherto untagged small effect variants.
Behavior change interventions to promote colorectal cancer (CRC) screening have targeted people in community and primary care settings, health care providers, and health systems. Randomized controlled trials provide the strongest evidence of intervention efficacy. The purpose of this integrative review was to evaluate trials of CRC screening interventions published between 1997 and 2007 and to identify knowledge gaps and future directions for research. Thirty-three randomized trials that met inclusion criteria were evaluated using a modified version of the TREND criteria. Significant intervention effects were reported in six out of ten trials focused on increasing fecal occult blood testing, four of seven trials focused on sigmoidoscopy or colonoscopy completion, and nine of 16 focused on completion of any screening test. Several effective interventions to promote CRC screening were identified. Future trials need to use theory to guide interventions, examine moderators and mediators, consistently report results, and use comparable outcome measures.
Colorectal cancer; screening; randomized trials; fecal occult blood test; sigmoidoscopy; colonoscopy
Diabetic neuropathy has varied clinical presentations. As clinicians we should be aware of the common as well as rare manifestations of this syndrome. Diabetic truncal neuropathy presenting as a painful pseudoabdominal mass can easily mislead clinicians who are unaware of this problem. Subsequently, this can lead to unnecessary investigations and discomfort to the patient. A good blood sugar control and judicious use of drugs for neuropathic pain along with physiotherapy usually gives good relief. It is mostly a self-limiting condition.
Diabetic truncal neuropathy; dysesthesia; pseudoabdominal mass
negative allosteric modulator; mGlu5; structure-activity-relationship; artificial neural network, addiction
This study identifies unique psychosocial characteristics among African American men that put the men at risk for non-adherence to colorectal cancer (CRC) screening (colonoscopy, sigmoidoscopy and FOBT). Subgroups sharing similar psychosocial characteristics may be targeted with specific intervention strategies aimed at increasing participation in screening, which could lead to increased early detection and decreased morbidity and mortality.
The male, African American veterans in our sample (n=260) had a mean age = 57.3 (SD=7.3). Our study employs latent class analysis (LCA), a quantitative-based, audience segmentation method to identify homogeneous subgroups of African American men with similar psychosocial characteristics related to CRC screening, potentially in need of different health information and intervention strategies. Latent class regression was used to examine the relationships among latent class structure and demographic characteristics.
There were four psychosocial risk classes across the three screening tests. A significant subset of men had psychosocial characteristics indicative of willingness to be screened for each test (Colonscopy=21.8%, Sigmoidoscopy=31.5%, FOBT=10.8%), although they were currently non-adherent. Men who received a past screening test, had greater than a high school education, or were married were more likely to be represented in a latent class indicative of being prepared for getting colonoscopy or sigmoidoscopy. Socio-demographic variables were unrelated to FOBT latent class structure.
Segmenting our sample of male African American veterans based on psychosocial risk characteristics can inform the development of more precisely targeted interventions for African American men who are non-adherent for CRC screening.
Colorectal cancer screening; Latent Class Analysis; Black men
To identify factors associated with diagnostic delay after an incomplete or abnormal mammogram among women participating in a state mammography screening program.
Retrospective case-control design using bivariate and multivariate logistic regression analyses to explore the associations between age, race, ethnicity, marital status, breast cancer history, and self-reported breast symptoms and delay.
A statewide program of free screening mammography for women who are under- or uninsured.
11,460 women enrolled in a free, statewide screening program from 2002–2006.
Using the Tennessee Breast and Cervical Cancer Screening Program database, further analyses were conducted.
Main Research Variables
The outcome measure was delay in completion of all diagnostic tests and was defined as women who did not complete testing within 60 days. Findings: Thirty-seven percent of women required follow-up, and of a subset used in the analysis, 30% experienced delay of more than 60 days. Controlling for marital status, age, and breast cancer history, women who experienced delay were more likely to be African American versus Caucasian (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.13, 1.85) or Hispanic (OR = 0.72, 95% CI = 0.55, 0.93) and to have self-reported breast symptoms (OR = 1.50, 95% CI = 1.27, 1.77).
In a sample of women with low income needing mammography follow-up, delay was associated with three intrapersonal variables, potentially reducing the effectiveness of mammography screening for women who were African American, or Hispanic, or had self-reported breast symptoms.
Nurses providing cancer screening examinations are uniquely positioned to assess the knowledge, beliefs, and resources of women using the program and to navigate women through barriers to completion. Knowledge of factors associated with delay is valuable for planning interventions and allocating program resources.
Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single nucleotide polymorphism (SNP) individually may not be well-suited to detect small effects of multiple SNPs, such as those operating within the same biological pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes.
To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWASes (N cases = 2,813, N deaths = 1,116), with a novel Principal Component – Gamma GSA method. Analysis was completed for all cases and then separately for high grade serous (HGS) histological subtype.
Analysis of the HGS subjects resulted in 43 gene sets with p<0.005 (1.7%); of these, 21 gene sets had p < 0.10 in both GWASes, including intracellular signaling pathway (p = 7.3 × 10−5) and macrolide binding (p = 6.2 ×10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (p=6.3 ×10−4) and macrolide binding (p=1.0×10−3). Of 18 gene sets with p<0.005 (0.7%), eight had p < 0.10 in both GWASes.
This research detected novel gene sets associated with EOC survival.
Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies.
pathway analysis; genetic association; GWAS; SNPs; gynecologic neoplasm
Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (Group I: mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7, and mGlu8). Non-competitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of SAR in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.
mGlu5; negative allosteric modulator; non-competitive antagonist; addiction
Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu1 and mGlu5; group II: mGlu2 and mGlu3; group III: mGlu4, mGlu6, mGlu7, and mGlu8). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson’s disease (PD), fragile X syndrome, and addiction. The development of structure−activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.
mGlu5; negative allosteric modulator; noncompetitive antagonist; addiction
There have been major advances in our understanding of the cellular and molecular biology of the human malignancies collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Perspective.
The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81–0.93, P-trend=7.4 × 10−5). No heterogeneity of effect across study centers was observed (phet=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.
We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003).
We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium.
No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies.
Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.
Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.
chromosome 3p; SNP; ovarian cancer; risk factors
Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER-positive breast cancer 0.6–5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERα, ERβ, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERα and ERβ SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERα SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050–4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104–4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738–6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256–3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis.
The association of invasive ovarian carcinoma risk with the functional polymorphism rs2228570 (aka rs10735810; FokI polymorphism) in the vitamin D receptor (VDR) gene was examined in 1820 white non-Hispanic cases and 3479 controls in a pooled analysis of five population-based case-control studies within the Ovarian Cancer Association Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Carriers of the rare T allele were at increased risk of ovarian carcinoma compared to women with the CC genotype in all studies combined; each copy of the T allele was associated with a modest 9% increased risk (OR=1.09; 95% CI:1.01–1.19; p=0.04). No significant heterogeneity among studies was observed (p=0.37) and, after excluding the dataset from the Hawaii study, the risk association for rs2228570 among replication studies was unchanged (OR=1.09; 95% CI: 1.00–1.19; p=0.06). A stronger association of rs2228570 with risk was observed among younger women (aged < 50 years versus 50 years or older) (p=0.04). In all studies combined, the increased risk per copy of the T allele among younger women was 24% (OR=1.24; 95% CI: 1.04–1.47; p=0.02). This association remained statistically significant after excluding the Hawaii data (OR= 1.20; 95% CI: 1.01–1.43; p=0.04). No heterogeneity of the association was observed by stage (p= 0.46), tumor histology (p=0.98), or time between diagnosis and interview (p=0.94). This pooled analysis provides further evidence that the VDR rs2228570 polymorphism might influence ovarian cancer susceptibility.
invasive ovarian carcinoma; vitamin D receptor gene (VDR); single nucleotide polymorphism; pooled analysis; case-control study
Single nucleotide polymorphisms (SNPs) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies.
We conducted a pooled analysis of previously-identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kilobases of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset.
After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk.
Common variants in these evaluated genes do not appear to be strongly associated with EOC risk.
This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be performed, and use of imputed SNP data should be considered.
miRNA processing; binding sites; inherited susceptibility; ovarian cancer; genetic variants
To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism (SNP) and the PROGINS allele.
Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies.
An international ovarian cancer consortium including studies from the Australia, Europe and the United States,
5,812 White female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies.
Main Outcome Measures
Genotypes for the +331C/T SNP and PROGINS allele and a history of endometriosis.
The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (OR=0.65; 95% CI: 0.43–0.98, p=0.042), whereas there was no association between the PROGINS allele and endometriosis (OR=0.94, 95% CI 0.76, 1.16).
Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced PR-A to PR-B ratio and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.
Endometriosis; progesterone receptor; ovarian cancer; PROGINS
Defective miRNA biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P<0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), a SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR=0.90, 95% CI: 0.82–0.98; P=0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B over-expression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be due to reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.
miRNA processing; inherited susceptibility; ovarian cancer; genetic variants
Herein we disclose the synthesis and SAR of a series of 4-(phenylsulfamoyl)phenylacetamide compounds as mGlu4 positive allosteric modulators (PAMs) that were identified via a functional HTS. An iterative parallel approach to these compounds culminated in the discovery of VU0364439 (11) which represents the most potent (19.8 nM) mGlu4 PAM reported to date.
Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu5 using a functional cell-based assay is described in this letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.