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BACKGROUND: The American Cancer Society recommends physicians inform average risk women about endometrial cancer (EC) risk on reaching menopause, but new diagnoses are rising fastest in women <50 years. Educating these women about EC risks requires knowledge of risk factors. However, EC in young women is rare and challenging to study in single study populations. METHODS: We included 13,846 incident EC patients (1,639 < 50 years) and 30,569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and EC risk. We created a risk score to evaluate the combined associations and population attributable fractions of these factors. RESULTS: In younger and older women, we observed positive associations with BMI and diabetes, and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women ≥50 years (PHet<0.01). BMI was the strongest risk factor [OR≥35 vs <25 kg/m2=5.57 (95% CI:4.33-7.16) for <50 years; OR≥35 vs <25 kg/m2=4.68 (95% CI : 4.30-5.09) for ≥50 years; PHet=0.14]. Possessing ≥4 risk factors was associated with â¼9-fold increased risk in women <50 years and â¼4-fold increased risk in women ≥50 years (PHet<0.01). Together, 59.1% of ECs in women <50 and 55.6% in women ≥50 were attributable to these factors. CONCLUSIONS: Our data confirm younger and older women share common EC risk factors. Early educational efforts centered on these factors may help mitigate the rising EC burden in young women.
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PURPOSE: There is compelling evidence that CD4+ and CD8+T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients. PATIENTS AND METHODS: The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n = 12) and unsupervised home-based walking arms (n = 12). Comprehensive flow cytometry was utilized to assess the frequency of CD4+ and CD8+T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints. RESULTS: Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4+ TIGIT+ to non-exhausted CD4+ (0.7 [0.6] to 0.6 [0.4], P = .04) and CD8+ PD1+ to non-exhausted CD8+ (1.8 [2.6] to 1.5 [2.0], P = .06), and in total exhausted CD8+ as a percent of total CD8+ (72.9 [21.9] to 68.3 [19.6], P < .01). CONCLUSIONS: This pilot study suggests that physical activity induces changes in MM patients' immune systems, potentially rendering a less exhausted T cell state.
Subject(s)
CD8-Positive T-Lymphocytes , Exercise , Multiple Myeloma , Humans , Multiple Myeloma/therapy , Multiple Myeloma/immunology , Male , Female , Middle Aged , Aged , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Biomarkers , Programmed Cell Death 1 Receptor/metabolism , Exercise Therapy/methods , Lymphocyte Activation Gene 3 Protein , T-Cell ExhaustionABSTRACT
BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. 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 endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer 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 ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer 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 endometrial cancer (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 versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer 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 endometrial cancer.
Subject(s)
Endometrial Neoplasms , Hypertension , Humans , Female , Endometrial Neoplasms/epidemiology , Risk Factors , Hypertension/epidemiology , Middle Aged , Case-Control Studies , Aged , Adult , IncidenceABSTRACT
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.
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ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma, is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine whether the risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a US population-based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (ORs) and 95% confidence intervals (CIs) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR, 0.70; 95% CI, 0.48-1.00; P < .05), fruits (excluding juice) and vegetables (OR, 0.69; 95% CI, 0.52-0.93; P = .02), vegetables (OR, 0.75; 95% CI, 0.56-0.99; P < .05), tomatoes (OR, 0.72; 95% CI, 0.51-1.00; P < .05), and cruciferous vegetables (OR, 0.44; 95% CI, 0.26-0.74; P < .01). Direct associations were observed for sugar-sweetened beverages (OR, 1.34; 95% CI, 1.00-1.78; P < .05), sugar-sweetened soft drinks (OR, 1.41; 95% CI, 1.01-1.96; P = .04), and artificially sweetened soft drinks (OR, 1.55; 95% CI, 1.04-2.33; P = .03). Our study shows that diet is potentially a modifiable risk factor for MGUS.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Humans , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Nutrition Surveys , Sweetening Agents , Case-Control Studies , Diet , Risk FactorsABSTRACT
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.
Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/genetics , Risk Factors , Risk Assessment , Case-Control StudiesABSTRACT
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.
Subject(s)
Aspirin , Ovarian Neoplasms , Humans , Female , Middle Aged , Aged , Genetic Predisposition to Disease , Ovarian Neoplasms/genetics , Carcinoma, Ovarian Epithelial/genetics , Logistic ModelsABSTRACT
Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.
Subject(s)
Pancreatic Neoplasms , Sugars , Humans , Artificially Sweetened Beverages , Sweetening Agents/adverse effects , Retrospective Studies , Risk Factors , Prospective Studies , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/etiology , Beverages/adverse effects , Beverages/analysis , Pancreatic NeoplasmsABSTRACT
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 26â204 control participants and 21â267 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.
Subject(s)
Ovarian Neoplasms , Pregnancy , Humans , Female , Carcinoma, Ovarian Epithelial/epidemiology , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/etiology , Ovarian Neoplasms/pathology , Risk Factors , Parity , Contraceptives, Oral/adverse effects , Case-Control StudiesABSTRACT
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.
Subject(s)
Endometrial Neoplasms , Ovarian Neoplasms , Male , Humans , Female , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/genetics , Risk Factors , ROC Curve , Ovarian Neoplasms/epidemiology , IncidenceABSTRACT
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.
Subject(s)
Endometriosis , Ovarian Neoplasms , Female , Humans , Endometriosis/diagnosis , Endometriosis/epidemiology , Endometriosis/chemically induced , Talc/adverse effects , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/etiology , Carcinoma, Ovarian Epithelial , Risk Factors , Case-Control Studies , EstrogensABSTRACT
PURPOSE: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS: Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS: Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION: This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.
Subject(s)
Endometriosis , Ovarian Neoplasms , Female , Humans , Aspirin/adverse effects , Endometriosis/complications , Endometriosis/drug therapy , Ovarian Neoplasms/drug therapy , Case-Control Studies , Risk FactorsABSTRACT
BACKGROUND: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. METHODS: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. RESULTS: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54). CONCLUSIONS: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. IMPACT: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Subject(s)
Carcinoma, Ovarian Epithelial/mortality , Inflammation/epidemiology , Ovarian Neoplasms/mortality , Aged , Female , Health Behavior , Humans , Middle Aged , Proportional Hazards Models , Risk AssessmentABSTRACT
PURPOSE: The incidence of esophageal adenocarcinoma (EAC) has risen substantially in recent decades, while the average 5-year survival remains only ~20%. Disease stage and treatment are the strongest prognostic factors. The role of lifestyle factors in relation to survival remains uncertain, with a handful of studies to date investigating associations with obesity, smoking, physical activity, diet, or medications. METHODS: This study included patients diagnosed with primary adenocarcinoma of the esophagus, gastroesophageal junction, or cardia (N = 371) at Roswell Park Comprehensive Cancer Center between 2003 and 2019. Leveraging extensive data abstracted from electronic medical records, epidemiologic questionnaires, and a tumor registry, we analyzed clinical, behavioral, and environmental exposures and evaluated stage-specific associations with survival. Survival distributions were visualized using Kaplan-Meier curves. Cox proportional hazards regression models adjusted for age, sex, stage, treatment, and comorbidities were used to estimate the association between each exposure and all-cause or cancer-specific mortality. RESULTS: Among patients presenting with localized/regional tumors (stages I-III), current smoking was associated with increased overall mortality risk (HR = 2.5 [1.42-4.53], p = 0.002), while current physical activity was linked to reduced risk (HR = 0.58 [0.35-0.96], p = 0.035). Among patients with stage IV disease, individuals reporting pre-diagnostic use of statins (HR = 0.62 [0.42-0.92], p = 0.018) or NSAIDs (HR = 0.61 [0.42-0.91], p = 0.016) had improved overall survival. Exploratory analyses suggested that high pre-diagnostic dietary consumption of broccoli, carrots, and fiber correlated with prolonged overall survival in patients with localized/regional disease. CONCLUSION: Our data suggest that lifestyle exposures may be differentially associated with EAC survival based on disease stage. Future investigation of larger, diverse patient cohorts is essential to validate these findings. Our results may help inform the development of lifestyle-based interventions to improve EAC prognosis and quality of life.
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Altered lipid metabolism has emerged as an important feature of ovarian cancer (OC), yet the translational potential of lipid metabolites to aid in diagnosis and triage remains unproven. We conducted a multi-level interrogation of lipid metabolic phenotypes in patients with adnexal masses, integrating quantitative lipidomics profiling of plasma and ascites with publicly-available tumor transcriptome data. Using Sciex Lipidyzer, we assessed concentrations of > 500 plasma lipids in two patient cohorts-(i) a pilot set of 100 women with OC (50) or benign tumor (50), and (ii) an independent set of 118 women with malignant (60) or benign (58) adnexal mass. 249 lipid species and several lipid classes were significantly reduced in cases versus controls in both cohorts (FDR < 0.05). 23 metabolites-triacylglycerols, phosphatidylcholines, cholesterol esters-were validated at Bonferroni significance (P < 9.16 × 10-5). Certain lipids exhibited greater alterations in early- (diacylglycerols) or late-stage (lysophospholipids) cases, and multiple lipids in plasma and ascites were positively correlated. Lipoprotein receptor gene expression differed markedly in OC versus benign tumors. Importantly, several plasma lipid species, such as DAG(16:1/18:1), improved the accuracy of CA125 in differentiating early-stage OC cases from benign controls, and conferred a 15-20% increase in specificity at 90% sensitivity in multivariate models adjusted for age and BMI. This study provides novel insight into systemic and local lipid metabolic differences between OC and benign disease, further implicating altered lipid uptake in OC biology, and advancing plasma lipid metabolites as a complementary class of circulating biomarkers for OC diagnosis and triage.
Subject(s)
Adnexa Uteri/pathology , Lipidomics , Ovarian Neoplasms/metabolism , Aged , Ascites/metabolism , CA-125 Antigen/blood , Case-Control Studies , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Lipids/blood , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/blood , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , ROC CurveABSTRACT
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.See related Spotlight by Cassatella, p. 725.
Subject(s)
Neutrophils/immunology , Ovarian Neoplasms/immunology , T-Lymphocytes/immunology , Trogocytosis/immunology , Tumor Escape , Adult , Cells, Cultured , Female , Humans , Lymphocyte Activation , Middle Aged , Neutrophil Activation , Neutrophils/metabolism , Ovarian Neoplasms/blood , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Primary Cell Culture , Tumor Microenvironment/immunology , Young AdultABSTRACT
BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death among women in the US, yet few modifiable risk factors have been established. Diets high in glycemic index (GI) and glycemic load (GL) have been linked to several cancers, but epidemiologic studies of ovarian cancer have yielded inconsistent results. OBJECTIVE: In this study, we aimed to examine associations between GI or GL and ovarian cancer. METHODS: We used prospective data from the Prostate, Lung, Colorectal, and Ovarian cohort. GI and GL were calculated from validated FFQs. Participants were women who were aged 60 to 74 y, did not have a history of cancer, and had both ovaries. Cox proportional hazard models were used to calculate HRs and 95% CIs for risk of ovarian cancer associated with quartiles of GI and GL. Analyses were performed separately for those who completed the dietary questionnaire at baseline (DQX) or later in the study (DHQ). RESULTS: From the DQX sample set, 181 cases were identified among 24,633 women with median follow-up of 12.1 y; there were 211 cases among 42,410 women in the DHQ set, with median follow-up of 8.9 y. After adjusting for age at dietary questionnaire completion, year of randomization, year of questionnaire, study center, and oral contraceptive use, the risk of ovarian cancer decreased by 43% (HR: 0.57; 95% CI: 0.37, 0.88) among those in the highest compared with those in the lowest quartile of GL (DQX). Those in the highest compared with those in the lowest quartile of GI (DHQ), had a 38% lower risk (HR: 0.62; 95% CI: 0.42, 1.00). CONCLUSIONS: We observed lower risk of ovarian cancer associated with higher GI and GL. Results should be interpreted with caution as they may have been influenced by limitations including lack of variability in dietary intake. Additional studies are needed to better understand what is driving these associations.
Subject(s)
Diet , Glycemic Index , Glycemic Load , Ovarian Neoplasms , Aged , Diet Surveys , Dietary Carbohydrates , Female , Humans , Lung , Middle Aged , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/etiology , Prospective Studies , Risk FactorsABSTRACT
BACKGROUND: Pancreatic cancer is a deadly malignancy with limited screening and few modifiable risk factors. The objective of this study was to investigate the association between a modifiable lifestyle behavior, cruciferous vegetable consumption, and pancreatic cancer, both overall and by subgroups based on non-modifiable, established risk factors. METHODS: We conducted a hospital-based, case-control study utilizing data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY) which included 183 pancreatic cancer patients and 732 cancer-free controls. Data were collected using a self-administered questionnaire including a 52-item food frequency questionnaire and other epidemiologic data. Multivariable logistic regression, adjusted for age, body mass index (BMI), sex, smoking status, total meat, and family history of pancreatic cancer, was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between cruciferous vegetable consumption and pancreatic cancer. Subgroup analyses were conducted by sex, smoking status, and BMI. RESULTS: We observed inverse associations between cruciferous vegetable intake and pancreatic cancer, with a significant 40% lower odds of pancreatic cancer among subjects consuming >1.5 servings per week (SPW) of raw cruciferous vegetables compared to those consuming less than 0.5 SPW (OR = 0.60, 95% CI: 0.39-0.93). Each additional SPW of total, raw, and cooked cruciferous vegetables was associated with a significant 7-15% lower odds of pancreatic cancer, with the strongest association seen in raw cruciferous vegetables (OR = 0.85, 95% CI: 0.75-0.95). We observed inverse associations between raw cruciferous vegetable intake and pancreatic cancer among people who were overweight, former smokers, and males, ranging from 50% to 59% lower odds. CONCLUSION: Consuming cruciferous vegetables, especially raw cruciferous vegetables, is a modifiable lifestyle behavior which may be inversely associated with pancreatic cancer, including among subgroups with other non- or not easily modifiable risk factors for this deadly malignancy.
Subject(s)
Brassicaceae , Diet/statistics & numerical data , Pancreatic Neoplasms/epidemiology , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Protective Factors , Risk Assessment , Surveys and QuestionnairesABSTRACT
BACKGROUND: Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered. METHODS: The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case-control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. RESULTS: Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50-0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (P trend < 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. CONCLUSIONS: DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. IMPACT: The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.
Subject(s)
Carcinoma, Ovarian Epithelial/prevention & control , Contraceptive Agents, Hormonal/administration & dosage , Medroxyprogesterone Acetate/administration & dosage , Ovarian Neoplasms/prevention & control , Adult , Carcinoma, Ovarian Epithelial/epidemiology , Case-Control Studies , Female , Humans , Middle Aged , Ovarian Neoplasms/epidemiology , Progestins/pharmacology , Risk AssessmentABSTRACT
Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1ß and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.