Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56–0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26–0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
Recent reports suggest that autoantibodies directed to aberrantly glycosylated mucins, in particular MUC1 and MUC4, are found in patients with colorectal cancer. There is, however, limited information on the autoantibody levels before clinical diagnosis, and their utility in cancer screening in the general population. In our study, we have generated O-glycosylated synthetic MUC1 and MUC4 peptides in vitro, to mimic cancer-associated glycoforms, and displayed these on microarrays. The assay’s performance was tested through an initial screening of serum samples taken from patients at the time of colorectal cancer diagnosis and healthy controls. Subsequently, the selected biomarkers were evaluated in a blinded nested case–control study using stored serum samples from among the 50,640 women randomized to the multimodal arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), where women gave annual blood samples for several years. Cases were 97 postmenopausal women who developed colorectal cancer after recruitment and were age-matched to 97 women without any history of cancer. MUC1-STn and MUC1-Core3 IgG autoantibodies identified cases with 8.2 and 13.4% sensitivity, respectively, at 95% specificity. IgA to MUC4 glycoforms were unable to discriminate between cases and controls in the UKCTOCS sera. Additional analysis was undertaken by combining the data of MUC1-STn and MUC1-Core3 with previously generated data on autoantibodies to p53 peptides, which increased the sensitivity to 32.0% at 95% specificity. These findings suggest that a combination of antibody signatures may have a role as part of a biomarker panel for the early detection of colorectal cancer.
MUC1; MUC4; glycosylation; early diagnosis; microarray; seromic profiling; biomarkers; cancer; autoantibodies; rectum; colon
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22-1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17-1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22–1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17–1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.191.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17–1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54–0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
Ovarian carcinoma is composed of five major histological types which associate with outcome and predict therapeutic response. Our aim was to evaluate histological type assessments across centres participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model.
Tissue microarrays (TMAs) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was performed for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histological type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review.
The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma (EC) by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of EC compared to HGSC became significant (RR 0.60, 95% CI 0.37–0.93, p=0.021), consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2.
Research cohorts, particularly those across different centres within consortia, show significant variability in original histological type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type.
Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology.
ovarian cancer; type; biomarker; immunohistochemistry; typing
To assess the efficacy of Korean Immigrants and Mammography—Culture-Specific Health Intervention (KIM-CHI), an educational program for Korean American (KA) couples designed to improve mammography uptake among KA women.
A two-group cluster randomized, longitudinal, controlled design.
50 KA religious organizations in the Chicago area.
428 married KA women 40 years of age or older who had not had a mammogram in the past year. The women and their husbands were recruited from 50 KA religious organizations.
Couples were randomly assigned to intervention or attention control groups. Those in the KIM-CHI program (n = 211 couples) were compared to an attention control group (n = 217 couples) at baseline, as well as at 6 and 15 months postintervention on mammogram uptake.
Main Research Variables
Sociodemographic variables and mammography uptake were measured. Level of acculturation was measured using the Suinn-Lew Asian Self-Identity Acculturation Scale. Researchers asked questions about healthcare resources and use, health insurance status, usual source of care, physical examinations in the past two years, family history of breast cancer, and history of mammography.
The KIM-CHI group showed statistically significant increases in mammography uptake compared to the attention control group at 6 months and 15 months postintervention.
The culturally targeted KIM-CHI program was effective in increasing mammogram uptake among nonadherent KA women.
Implications for Nursing
Nurses and healthcare providers should consider specific health beliefs as well as inclusion of husbands or significant others. They also should target education to be culturally relevant for KA women to effectively improve frequency of breast cancer screening.
breast cancer; clinical trials; mammography; Korean American; prevention; detection
Several studies suggest that overall and central-obesity are associated with increased breast cancer (BC) risk in postmenopausal-women. However, there are no studies investigating changes of central obesity and BC. We report on the association of BC risk with self-reported skirt size (SS; waist-circumference proxy) changes between 20s and postmenopausal-age.
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) involving the nine trial centres in England.
Postmenopausal-women aged >50 with no known history of BC prior to or on the day of completion of the study-entry questionnaire.
At recruitment and at study entry, women were asked to complete a questionnaire. Women were followed-up via ‘flagging’ at the NHS Information Centre in England and the Hospital Episode Statistics.
Time to initial BC diagnosis.
Between 2 January 2005 and 1 July 2010, 92 834 UKCTOCS participants (median age 64.0) completed the study-entry questionnaire. During median follow-up of 3.19 years (25th–75th centile: 2.46–3.78), 1090 women developed BC. Model adjusted analysis for potential confounders showed body mass index (BMI) at recruitment to UKCTOCS (HR for a 5 unit change=1.076, 95% CI 1.012 to 1.136), current SS at study entry (HR=1.051; 95% CI 1.014 to 1.089) and change in SS per 10 years (CSS) (HR=1.330; 95% CI 1.121 to 1.579) were associated with increased BC risk but not SS at 25 (HR=1.006; 95% CI 0.958 to 1.056). CSS was the most predictive singe adiposity measure and further analysis including both CSS and BMI in the model revealed CSS remained significant (HR=1.266; 95% CI 1.041 to 1.538) but not BMI (HR=1.037; 95% CI 0.970 to 1.109).
CSS is associated with BC risk independent of BMI. A unit increase in UK SS (eg, 12–14) every 10-years between 25 and postmenopausal-age is associated with postmenopausal BC risk by 33%. Validation of these results could provide women with a simple and easy to understand message.
Trial registration number
Background: The purpose of this study was to identify beliefs about breast cancer, screening practices, and factors associated with mammography use among first-generation immigrant Muslim women in Chicago, IL.
Methods: A convenience sample of 207 first-generation immigrant Muslim women (Middle Eastern 51%; South Asian 49%) completed a culturally adapted questionnaire developed from established instruments. The questionnaire was administered in Urdu, Hindi, Arabic, or English, based on participant preference. Internal-consistency reliability was demonstrated for all scales (alpha coefficients ranged from 0.64 to 0.91). Associations between enabling, predisposing, and need variables and the primary outcome of mammography use were explored by fitting logistic regression models.
Results: Although 70% of the women reported having had a mammogram at least once, only 52% had had one within the past 2 years. Four factors were significant predictors of ever having had a mammogram: years in the United States, self-efficacy, perceived importance of mammography, and intent to be screened. Five factors were significant predictors of adherence (having had a mammogram in the past 2 years): years in the United States, having a primary care provider, perceived importance of mammography, barriers, and intent to be screened.
Conclusions: This article sheds light on current screening practices and identifies theory-based constructs that facilitate and hinder Muslim women's participation in mammography screening. Our findings provide insights for reaching out particularly to new immigrants, developing patient education programs grounded in culturally appropriate approaches to address perceived barriers and building women's self-efficacy, as well as systems-level considerations for ensuring access to primary care providers.
BRCA1 mutation carriers have an 85% risk of developing breast cancer but the risk of developing non-hereditary breast cancer is difficult to assess. Our objective is to test whether a DNA methylation (DNAme) signature derived from BRCA1 mutation carriers is able to predict non-hereditary breast cancer.
In a case/control setting (72 BRCA1 mutation carriers and 72 BRCA1/2 wild type controls) blood cell DNA samples were profiled on the Illumina 27 k methylation array. Using the Elastic Net classification algorithm, a BRCA1-mutation DNAme signature was derived and tested in two cohorts: (1) The NSHD (19 breast cancers developed within 12 years after sample donation and 77 controls) and (2) the UKCTOCS trial (119 oestrogen receptor positive breast cancers developed within 5 years after sample donation and 122 controls).
We found that our blood-based BRCA1-mutation DNAme signature applied to blood cell DNA from women in the NSHD resulted in a receiver operating characteristics (ROC) area under the curve (AUC) of 0.65 (95% CI 0.51 to 0.78, P = 0.02) which did not validate in buccal cells from the same individuals. Applying the signature in blood DNA from UKCTOCS volunteers resulted in AUC of 0.57 (95% CI 0.50 to 0.64; P = 0.03) and is independent of family history or any other known risk factors. Importantly the BRCA1-mutation DNAme signature was able to predict breast cancer mortality (AUC = 0.67; 95% CI 0.51 to 0.83; P = 0.02). We also found that the 1,074 CpGs which are hypermethylated in BRCA1 mutation carriers are significantly enriched for stem cell polycomb group target genes (P <10-20).
A DNAme signature derived from BRCA1 carriers is able to predict breast cancer risk and death years in advance of diagnosis. Future studies may need to focus on DNAme profiles in epithelial cells in order to reach the AUC thresholds required of preventative measures or early detection strategies.
Hopelessness is an important construct in psychosocial epidemiology, but there is great pressure on the length of questionnaire measures in large-scale population and clinical studies. We examined the validity and test–retest reliability of two brief measures of hopelessness, an existing negatively worded two-item measure of hopelessness (Brief-H-Neg) and a positively worded version of the same instrument (Brief-H-Pos).
Control arm of the UK Collaborative Trial of Ovarian Cancer Screening.
A non-clinical research-based sample of 5000 postmenopausal women selected from 56 512 participants.
Primary and secondary outcome measures
Spearman's rank correlation of brief measures of hopelessness with the Beck Hopelessness Scale (BHS). Spearman's rank correlation with the Centre for Epidemiological Studies Depression Scale (CES-D) and change in mean score on repeat testing.
Two short hopelessness measures, a negatively worded brief measure of hopelessness (Brief-H-Neg) and a positively worded brief measure of hopelessness (Brief-H-Pos), were administered by postal questionnaire to 5000 women together with the 20-item BHS and 20-item CES-D. The Brief-H-Neg and Brief-H-Pos were readministered to 500 women after a 2-week interval.
2413 postmenopausal women (mean age 68.9 years) completed the questionnaire. The Brief-H-Neg and Brief-H-Pos correlated 0.93 and 0.87 with the BHS after correction for attenuation and their association with the CES-D mirrored that seen with the BHS (Spearman's rank correlation 0.88 and 0.68, respectively). There was no change in mean scores on the two measures with repeat testing in the 433 women who completed them and test–retest reliability was good (intraclass correlations Brief-H-Neg 0.67 and Brief-H-Pos 0.72).
These findings provide support for the validity of the Brief-H-Neg and Brief-H-Pos. These brief measures are likely to be useful in large population studies assessing hopelessness.
Trial registration number
Epidemiology; Mental Health
The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.
We used data from 21 case–control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model.
Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03–1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39–2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12–1.50). For these histological types, consistent dose– response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer.
Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.
Case–control studies; Histological type; Ovarian neoplasms; Smoking
Ovarian cancer is a lethal disease comprised of distinct histopathological types. There are few established biomarkers of ovarian cancer prognosis, in part because subtype-specific associations may have been obscured in studies combining all subtypes. We examined whether progesterone receptor (PR) and estrogen receptor (ER) protein expression were associated with subtype-specific survival in the international Ovarian Tumor Tissue Analysis (OTTA) consortium.
PR and ER were assessed by central immunohistochemical analysis of tissue microarrays for 2933 women with invasive epithelial ovarian cancer from 12 study sites. Negative, weak, and strong expression were defined as positive staining in <1%, 1–50%, and ≥50% of tumor cell nuclei, respectively. Hazard ratios (HRs) for ovarian cancer death were estimated using Cox regression stratified by site and adjusted for age, stage, and grade.
PR expression was associated with improved survival for endometrioid (EC; p<0·0001) and high-grade serous carcinoma (HGSC; p=0·0006), and ER expression was associated with improved EC survival (p<0·0001); no significant associations were found for mucinous, clear cell, or low-grade serous carcinoma. EC patients with hormone receptor (PR and/or ER) positive (weak or strong) versus negative tumors had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·33; 95% CI, 0·21–0·51; p<0·0001). HGSC patients with strong versus weak or negative tumor PR expression had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·71; 95% CI, 0·55–0·91; p=0·0061).
PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to determine whether hormone receptor status predicts response to endocrine therapy, and can guide personalized treatment for ovarian cancer.
Carraressi Foundation, US National Institutes of Health, National Health and Medical Research Council of Australia, UK National Institute for Health Research, and others.
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
Evidence of a mortality benefit continues to elude ovarian cancer (OC) screening. Data from the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial which used a screening strategy incorporating CA125 cut-off and transvaginal ultrasound has not shown mortality benefit. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is using the Risk of Ovarian Cancer (ROC) time series algorithm to interpret CA125, which has shown an encouraging sensitivity and specificity however the mortality data will only be available in 2015. The article explores the impact of growing insights into disease aetiology and evolution and biomarker discovery on future screening strategies. A better understanding of the target lesion, improved design of biomarker discovery studies, a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as cervical cytology and targeted imaging and use of time series algorithms for interpreting markers profile suggests that a new era in screening is underway.
•Ovarian cancer screening using CA125 cut-off has shown no mortality benefit.•Initial results using a time-series algorithm have been encouraging.•Cancer-specific biomarkers, novel biospecimens, targeted imaging to detect precursor lesion/low-volume disease are likely to be central to future screening strategies.
Ovarian cancer; Screening; Biomarkers; Imaging; UKCTOCS
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.
Whilst previous studies have reported that higher body-mass index (BMI)
increases a woman’s risk of developing ovarian cancer, associations for
the different histological subtypes have not been well defined. As the
prevalence of obesity has increased dramatically, and classification of ovarian
histology has improved in the last decade, we sought to examine the association
in a pooled analysis of recent studies participating in the Ovarian Cancer
Association Consortium. We evaluated the association between BMI (recent,
maximum, and in young adulthood) and ovarian cancer risk using original data
from 15 case-control studies (13,548 cases, 17,913 controls). We combined
study-specific adjusted odds ratios (ORs) using a random–effects model.
We further examined the associations by histological subtype, menopausal status
and post-menopausal hormone use. High BMI (all time-points) was associated with
increased risk. This was most pronounced for borderline serous (recent BMI:
pooled OR=1.24 per 5kg/m2; 95%CI 1.18–1.30),
invasive endometrioid (1.17; 1.11–1.23) and invasive mucinous (1.19;
1.06–1.32) tumours. There was no association with serous invasive cancer
overall (0.98; 0.94–1.02), but increased risks for low grade serous
invasive tumours (1.13, 1.03–1.25) and in pre-menopausal women (1.11;
1.04–1.18). Among post–menopausal women, the associations did
not differ between HRT users and non–users. Whilst obesity appears to
increase risk of the less common histological subtypes of ovarian cancer, it
does not increase risk of high grade invasive serous cancers, and reducing BMI
is therefore unlikely to prevent the majority of ovarian cancer deaths. Other
modifiable factors must be identified to control this disease.
ovarian cancer; obesity; body mass index
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer.
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.