Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer (EC) are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for EC. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of EC remains unclear. In this study we evaluated hypertension as an independent risk factor for EC and whether this association is modified by other established risk factors. METHODS: We included 15,631 EC cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between hypertension and EC and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of EC (OR=1.14, 95% CI:1.09-1.19). There was significant heterogeneity by study design (Phet<0.01), with a stronger magnitude of association observed among case-control vs. cohort studies. Stronger associations were also noted for pre-/peri-menopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with EC risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for EC.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Night shift work, sleep duration and endometrial cancer risk: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.

Global epidemiologic patterns of oropharyngeal cancer incidence trends.

BACKGROUND: The emergence of human papillomavirus (HPV)-positive oropharyngeal cancer and evolving tobacco use patterns have changed the landscape of head and neck cancer epidemiology internationally. We investigated updated trends in oropharyngeal cancer incidence worldwide. METHODS: We analyzed cancer incidence data between 1993 and 2012 from 42 countries using the Cancer Incidence in Five Continents database volumes V through XI. Trends in oropharyngeal cancer incidence were compared with oral cavity cancers and lung squamous cell carcinomas using log-linear regression and age period-cohort modeling. RESULTS: In total, 156 567 oropharyngeal cancer, 146 693 oral cavity cancer, and 621 947 lung squamous cell carcinoma patients were included. Oropharyngeal cancer incidence increased (P < .05) in 19 and 23 countries in men and women, respectively. In countries with increasing male oropharyngeal cancer incidence, all but 1 had statistically significant decreases in lung squamous cell carcinoma incidence, and all but 2 had decreasing or nonsignificant net drifts for oral cavity cancer. Increased oropharyngeal cancer incidence was observed both in middle-aged (40-59 years) and older (≥60 years) male cohorts, with strong nonlinear birth cohort effects. In 20 countries where oropharyngeal cancer incidence increased for women and age period-cohort analysis was possible, 13 had negative or nonsignificant lung squamous cell carcinoma net drifts, including 4 countries with higher oropharyngeal cancer net drifts vs both lung squamous cell carcinoma and oral cavity cancer (P < .05 for all comparisons). CONCLUSIONS: Increasing oropharyngeal cancer incidence is seen among an expanding array of countries worldwide. In men, increased oropharyngeal cancer is extending to older age groups, likely driven by human papillomavirus-related birth cohort effects. In women, more diverse patterns were observed, suggesting a complex interplay of risks factors varying by country, including several countries where female oropharyngeal cancer increases may be driven by HPV.

A framework for assessing interactions for risk stratification models: the example of ovarian cancer.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States.

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

Folate Intake and Ovarian Cancer Risk among Women with Endometriosis: A Case-Control Study from the Ovarian Cancer Association Consortium.

BACKGROUND: Although folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in precancerous lesions. Women with endometriosis (a potential precancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. METHODS: We conducted a pooled analysis of six case-control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals for the association between folate intake (dietary, supplemental, and total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. RESULTS: Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis [OR, 1.37 (1.01-1.86)] but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. CONCLUSIONS: High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. IMPACT: Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

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.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility.

Importance: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. Objective: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. Design, Setting, and Participants: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. Exposures: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. Main Outcomes and Measures: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. Results: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. Conclusions and Relevance: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

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.

Single-cell transcriptomic analysis of endometriosis.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

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.

Lifestyle and personal factors associated with having macroscopic residual disease after ovarian cancer primary cytoreductive surgery.

OBJECTIVE: The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery. METHODS: This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS. RESULTS: Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53). CONCLUSIONS: The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.

Incidence and Clearance of Anal Human Papillomavirus Infection in 16 164 Individuals, According to Human Immunodeficiency Virus Status, Sex, and Male Sexuality: An International Pooled Analysis of 34 Longitudinal Studies.

BACKGROUND: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized. METHODS: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants. RESULTS: Human papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection. CONCLUSIONS: This robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

Age-Specific Prevalence of Anal and Cervical Human Papillomavirus Infection and High-Grade Lesions in 11 177 Women by Human Immunodeficiency Virus Status: A Collaborative Pooled Analysis of 26 Studies.

BACKGROUND: Age-specific data on anal, and corresponding cervical, human papillomavirus (HPV) infection are needed to inform female anal cancer prevention. METHODS: We centrally reanalyzed individual-level data from 26 studies reporting HPV prevalence in paired anal and cervical samples by human immunodeficiency virus (HIV) status and age. For women with HIV (WWH) with anal high-grade squamous intraepithelial lesions or worse (HSIL+), we also investigated concurrent cervical cytopathology. RESULTS: In HIV-negative women, HPV16 prevalence decreased significantly with age, both at anus (4.3% at 15-24 years to 1.0% at ≥55 years; ptrend = 0.0026) and cervix (7.4% to 1.7%; ptrend < 0.0001). In WWH, HPV16 prevalence decreased with age at cervix (18.3% to 7.2%; ptrend = 0.0035) but not anus (11.5% to 13.9%; ptrend = 0.5412). Given anal HPV16 positivity, concurrent cervical HPV16 positivity also decreased with age, both in HIV-negative women (ptrend = 0.0005) and WWH (ptrend = 0.0166). Among 48 WWH with HPV16-positive anal HSIL+, 27 (56%) were cervical high-risk HPV-positive, including 8 with cervical HPV16, and 5 were cervical HSIL+. CONCLUSIONS: Age-specific shifts in HPV16 prevalence from cervix to anus suggest that HPV infections in the anus persist longer, or occur later in life, than in the cervix, particularly in WWH. This is an important consideration when assessing the utility of cervical screening results to stratify anal cancer risk.

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.

BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Effects of risk factors for ovarian cancer in women with and without endometriosis.

OBJECTIVE: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. DESIGN: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. SETTING: Population-based. PATIENT(S): We included 8,500 women with ovarian cancer, 13,592 control women. INTERVENTION(S): Ten well-established ovarian cancer risk factors. MAIN OUTCOME MEASURE(S): Risk of ovarian cancer for women with and without endometriosis. RESULT(S): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). CONCLUSION(S): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

National prevalence of IC/BPS in women and men utilizing veterans health administration data.

Importance: Interstitial cystitis/bladder pain syndrome (IC/BPS) is an immense burden to both patients and the American healthcare system; it is notoriously difficult to diagnose. Prevalence estimates vary widely (150-fold range in women and >500-fold range in men). Objectives: We aimed to create accurate national IC/BPS prevalence estimates by employing a novel methodology combining a national population-based dataset with individual chart abstraction. Study design: In this epidemiological survey, all living patients, with ≥2 clinic visits from 2016 to 2018 in the Veterans Health Administration, with an ICD-9/10 code for IC/BPS (n = 9,503) or similar conditions that may represent undiagnosed IC/BPS (n = 124,331), were identified (other were controls n = 5,069,695). A detailed chart review of random gender-balanced samples confirmed the true presence of IC/PBS, which were then age- and gender-matched to the general US population. Results: Of the 5,203,529 patients identified, IC/BPS was confirmed in 541 of 1,647 sampled charts with an IC/BPS ICD code, 10 of 382 charts with an ICD-like code, and 3 of 916 controls. After age- and gender-matching to the general US population, this translated to national prevalence estimates of 0.87% (95% CI: 0.32, 1.42), with female and male prevalence of 1.08% (95% CI: 0.03, 2.13) and 0.66% (95% CI: 0.44, 0.87), respectively. Conclusions: We estimate the prevalence of IC/BPS to be 0.87%, which is lower than prior estimates based on survey data, but higher than prior estimates based on administrative data. These potentially represent the most accurate estimates to date, given the broader and more heterogeneous population studied and our novel methodology of combining in-depth chart abstraction with administrative data.