Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Risk prediction models for endometrial cancer: development and validation in an international consortium.

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). CONCLUSIONS: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Pre- and postsurgical medical therapy for endometriosis surgery.

BACKGROUND: Endometriosis is a common gynaecological condition affecting 10% to 15% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is combining surgery and medical therapy to reduce the recurrence of endometriosis. Though the combination of surgery and medical therapy appears to be beneficial, there is a lack of clarity about the appropriate timing of when medical therapy should be used in relation with surgery, that is, before, after, or both before and after surgery, to maximize treatment response. OBJECTIVES: To determine the effectiveness of medical therapies for hormonal suppression before, after, or both before and after surgery for endometriosis for improving painful symptoms, reducing disease recurrence, and increasing pregnancy rates. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in November 2019 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) which compared medical therapies for hormonal suppression before, after, or before and after, therapeutic surgery for endometriosis. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Where possible, we combined data using risk ratio (RR), standardized mean difference or mean difference (MD) and 95% confidence intervals (CI). Primary outcomes were: painful symptoms of endometriosis as measured by a visual analogue scale (VAS) of pain, other validated scales or dichotomous outcomes; and recurrence of disease as evidenced by EEC (Endoscopic Endometriosis Classification), rAFS (revised American Fertility Society), or rASRM (revised American Society for Reproductive Medicine) scores at second-look laparoscopy. MAIN RESULTS: We included 26 trials with 3457 women with endometriosis. We used the term "surgery alone" to refer to placebo or no medical therapy. Presurgical medical therapy compared with placebo or no medical therapy Compared to surgery alone, we are uncertain if presurgical medical hormonal suppression reduces pain recurrence at 12 months or less (dichotomous) (RR 1.10, 95% CI 0.72 to 1.66; 1 RCT, n = 262; very low-quality evidence) or whether it reduces disease recurrence at 12 months - total (AFS score) (MD -9.6, 95% CI -11.42 to -7.78; 1 RCT, n = 80; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression decreases disease recurrence at 12 months or less (EEC stage) compared to surgery alone (RR 0.88, 95% CI 0.78 to 1.00; 1 RCT, n = 262; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression improves pregnancy rates compared to surgery alone (RR 1.16, 95% CI 0.99 to 1.36; 1 RCT, n = 262; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous) or disease recurrence at 12 months or less. Postsurgical medical therapy compared with placebo or no medical therapy We are uncertain about the improvement observed in pelvic pain at 12 months or less (continuous) between postsurgical medical hormonal suppression and surgery alone (MD -0.48, 95% CI -0.64 to -0.31; 4 RCTs, n = 419; I2 = 94%; very low-quality evidence). We are uncertain if there is a difference in pain recurrence at 12 months or less (dichotomous) between postsurgical medical hormonal suppression and surgery alone (RR 0.85, 95% CI 0.65 to 1.12; 5 RCTs, n = 634; I2 = 20%; low-quality evidence). We are uncertain if postsurgical medical hormonal suppression improves disease recurrence at 12 months - total (AFS score) compared to surgery alone (MD -2.29, 95% CI -4.01 to -0.57; 1 RCT, n = 51; very low-quality evidence). Disease recurrence at 12 months or less may be reduced with postsurgical medical hormonal suppression compared to surgery alone (RR 0.30, 95% CI 0.17 to 0.54; 4 RCTs, n = 433; I2 = 58%; low-quality evidence). We are uncertain about the reduction observed in disease recurrence at 12 months or less (EEC stage) between postsurgical medical hormonal suppression and surgery alone (RR 0.80, 95% CI 0.70 to 0.91; 1 RCT, n = 285; very low-quality evidence). Pregnancy rate is probably increased with postsurgical medical hormonal suppression compared to surgery alone (RR 1.22, 95% CI 1.06 to 1.39; 11 RCTs, n = 932; I2 = 24%; moderate-quality evidence). Pre- and postsurgical medical therapy compared with surgery alone or surgery and placebo There were no trials identified in the search for this comparison. Presurgical medical therapy compared with postsurgical medical therapy We are uncertain about the difference in pain recurrence at 12 months or less (dichotomous) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.40, 95% CI 0.95 to 2.07; 2 RCTs, n = 326; I2 = 2%; low-quality evidence). We are uncertain about the difference in disease recurrence at 12 months or less (EEC stage) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.10, 95% CI 0.95 to 1.28; 1 RCT, n = 273; very low-quality evidence). We are uncertain about the difference in pregnancy rate between postsurgical and presurgical medical hormonal suppression therapy (RR 1.05, 95% CI 0.91 to 1.21; 1 RCT, n = 273; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous), disease recurrence at 12 months - total (AFS score) or disease recurrence at 12 months or less (dichotomous). Postsurgical medical therapy compared with pre- and postsurgical medical therapy There were no trials identified in the search for this comparison. Serious adverse effects for medical therapies reviewed There was insufficient evidence to reach a conclusion regarding serious adverse effects, as no studies reported data suitable for analysis. AUTHORS' CONCLUSIONS: Our results indicate that the data about the efficacy of medical therapy for endometriosis are inconclusive, related to the timing of hormonal suppression therapy relative to surgery for endometriosis. In our various comparisons of the timing of hormonal suppression therapy, women who receive postsurgical medical therapy compared with no medical therapy or placebo may experience benefit in terms of disease recurrence and pregnancy. There is insufficient evidence regarding hormonal suppression therapy at other time points in relation to surgery for women with endometriosis.

Self-reported Prostate Cancer Progression Status Is Accurate: A Validation Study.

BACKGROUND: Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression. METHODS: We conducted a validation study of self-reported prostate cancer progression in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and in a prostate cancer cohort enrolled in a Fred Hutchinson Cancer Research Center (FHCRC)-based study. We calculated measures of validity for self-reported progression, including sensitivity, specificity, positive predictive value, and negative predictive value using medical records as the gold standard. RESULTS: Our results suggest that ascertaining prostate cancer progression-related events (i.e., prostate-specific antigen elevation, recurrence, metastasis, and use of secondary treatment) through self-report may be a viable option for identifying men whose disease has progressed after diagnosis or initial therapy, particularly when multiple questions related to progression are included in the assessment (aggregate cluster of questions: sensitivity = 0.76 [PLCO]; 0.93 [FHCRC], specificity = 0.80 [PLCO]; 0.97 [FHCRC]). With an aggregate positive predictive value of 0.50 (PLCO), however, our PLCO results suggest that additional medical record verification of self-reported progression events may be necessary to rule out false positives. Most individuals reporting no evidence of progression-related events, however, were true negatives (aggregate negative predictive value = 0.92 [PLCO]; 0.98 [FHCRC]). Thus, there may be limited utility to investing resources in chart review to confirm self-reported nonevents. CONCLUSION: Ascertaining prostate cancer progression through self-report provides an efficient and valid approach to enhancing existing cancer cohorts with updated data on progression status. See video abstract at, http://links.lww.com/EDE/B658.

Risk of Prostate Cancer-related Death Following a Low PSA Level in the PLCO Trial.

Longer-than-annual screening intervals have been suggested to improve the balance of benefits and harms in prostate cancer screening. Many researchers, societies, and guideline committees have suggested that screening intervals could depend on the prostate-specific antigen (PSA) result. We analyzed data from men (N = 33,897) ages 55-74 years with a baseline PSA test in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial (United States, 1993-2001). We estimated 5- and 10-year risks of aggressive cancer (Gleason ≥8 and/or stage III/IV) and 15-year risks of prostate cancer-related mortality for men with baseline PSA ≤ 0.5 ng/mL (N = 4,862), ≤1 ng/mL (N = 15,110), and 1.01-2.5 ng/mL (N = 12,422). A total of 217 men died from prostate cancer through 15 years, although no men with PSA ≤ 1 ng/mL died from prostate cancer within 5 years [95% confidence interval (CI), 0.00%-0.03%]. The 5-year incidence of aggressive disease was low (0.08%; 95% CI, 0.03%-0.12%) for men with PSA ≤ 1 ng/mL, and higher for men with baseline PSA 1.01-2.5 ng/mL (0.51%; 95% CI, 0.38%-0.74%). No men aged ≥65 years with PSA ≤ 0.5 ng/mL died from prostate cancer within 15 years (95% CI, 0.00%-0.32%), and their 10-year incidence of aggressive disease was low (0.25%; 95% CI, 0.00%-0.53%). Compared with white men, black men with PSA ≤ 1 ng/mL had higher 10-year rates of aggressive disease (1.6% vs. 0.4%; P < 0.01). Five-year screening intervals may be appropriate for the 45% of men with PSA ≤ 1 ng/mL. Men ages ≥65 years with PSA ≤ 0.5 ng/mL could consider stopping screening. Substantial risk disparities suggest appropriate screening intervals could depend on race/ethnicity.

Metastatic prostate cancer at diagnosis and through progression in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial assessed the effect of screening with prostate-specific antigen and a digital rectal examination on prostate cancer mortality. Another endpoint of interest was the burden of total metastatic disease. METHODS: All men in PLCO were assessed for metastatic prostate cancer at diagnosis; men with clinical stage I/II disease were assessed for metastatic progression. The rate of total metastatic disease was defined as metastases found either at diagnosis or through progression divided by person-years (PYs) of follow-up for all men in the trial. Metastatic progression rates were computed among men with clinical stage I/II prostate cancer. Survival among men with metastases at diagnosis was compared with survival among men with metastatic progression. RESULTS: Among 38,340 men in the intervention arm and 38,343 men in the control arm in PLCO, there were 4974 and 4699 prostate cancer cases, respectively. The rates of total metastatic disease were 4.72 and 4.83 per 10,000 PYs in the intervention and control arms, respectively (rate ratio, 0.98; 95% CI, 0.81-1.18). The rates of metastatic progression among men with clinical stage I/II prostate cancer were 43.7 and 50.5 per 10,000 PYs in the intervention and control arms, respectively (P = .30). Prostate cancer-specific 5- and 10-year survival rates were significantly worse for men with metastatic progression (24% and 19%, respectively) than men with metastases at diagnosis (40% and 26%, respectively). CONCLUSIONS: Rates of total metastatic disease and metastatic progression were similar across arms in PLCO. Survival was worse for men with metastatic progression in comparison with those with metastatic disease at diagnosis.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Identification of nine new susceptibility loci for endometrial cancer.

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Secondary prostate cancer screening outcomes by race in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial.

BACKGROUND: Despite disparities in prostate cancer incidence and mortality rates between black and white men, there is still insufficient data available to assess potential differences in the benefits and harms of prostate cancer screening by race. Although the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial is underpowered to detect a difference by race in prostate-cancer specific mortality, because of the large study size, there are still sufficient numbers to examine secondary screening outcomes. The objective of this analysis is to examine whether differences exist between black and white participants with respect to screening false-positive rates, biopsy follow-up of men with positive screens, tumor characteristics, and overdiagnosis of prostate cancer. METHODS: Participants from the PLCO included men aged 55-74 years at baseline. Cancer diagnoses and deaths were identified through study update questionnaires, records of biopsy procedures, and linkage with the National Death Index. Cancer characteristics were obtained by medical abstractors. We used chi-squared tests to assess differences in false-positive rates, biopsy follow-up, and tumor characteristics. We used Cox proportional hazards models to compare incidence and mortality rates adjusting for age and survival rates adjusting for Gleason scores. RESULTS: Black men were slightly more likely (14.5%) to have a false-positive PSA test compared to white men (12.4%; P = 0.02) but less likely to have a false-positive digital rectal exam (DRE) (10.9% vs 14.2%, respectively; P < 0.001). Among all men who were screened, black men were significantly more likely to undergo a biopsy than white men (16.5% vs 13.8%, respectively [P = 0.003]) but there was no difference when limited to those with a positive PSA test. Prostate cancer tumors were more likely to be aggressive and to have metastasized in black men compared to white men. Disparities in incidence, mortality, and survival rates were comparable to those seen in population-based data. CONCLUSIONS: There was evidence that false-positive test results differed by race and screening test. Consistent with previous studies, cancer outcomes, and tumor characteristics were all more unfavorable in black men.

Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men.

INTRODUCTION: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. METHODS: Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. RESULTS: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. CONCLUSION: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Novel murine xenograft model for the evaluation of stem cell therapy for profound dysphagia.

OBJECTIVES/HYPOTHESIS: Dysphagia is common and costly. Treatments are limited and innovative therapies are required. The tongue is essential for safe, effective swallowing and is a natural target for regenerative therapy. Muscle-derived stem cells (MDSCs) hold potential to restore dynamic function, and their application in the damaged tongue is appealing. We examined the safety and efficacy of human MDSC implantation into a novel mouse tongue model. STUDY DESIGN: Animal study. METHODS: Adult immune-deficient mice were randomized to surgical (hemiglossectomy) and nonsurgical groups. Animals underwent lingual injection of human MDSCs or saline (control). Groups were followed for 12 weeks. The primary outcome was MDSC survival measured by an in vivo imaging system (IVIS). Secondary outcomes included animal survival and weight. Comparisons were made using a Mann-Whitney U test with an α of .05. RESULTS: Human MDSCs survived to the endpoint demonstrating 132% ± 465% and 15% ± 11% bioluminescence by IVIS at 12 weeks in hemiglossectomy and nonsurgical groups, respectively. All but one animal (hemiglossectomy with saline injection) survived to the study endpoint. Mean weight increased from baseline in all groups, with the greatest change observed in hemiglossectomy mice with MDSC injection (baseline 24.5 g ± 3.9 g; delta 5.9 g ± 4.6 g), exceeding the weight gain seen in surgical control mice (baseline 24.9 g ± 4.2 g, delta 2.7 g ± 1.4 g) (P = .04). CONCLUSIONS: MDSCs exhibited over 100% survival at 3 months when injected into an immune-deficient hemiglossectomy mouse model. Tongue-injured animals injected with MDSCs exhibited superior weight gain after hemiglossectomy than control animals (P < .05). These data support further investigation into the use of autologous MDSCs as a potential treatment for dysphagia secondary to tongue weakness and fibrosis LEVEL OF EVIDENCE: NA Laryngoscope, 127:E359-E363, 2017.