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Mesonephric-type (or -like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four-marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four-marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376-0.727) with the integration of the four-marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first-line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62-5.85; p < 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended.
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Biomarcadores de Tumor , Neoplasias Ováricas , Factor de Transcripción PAX2 , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/mortalidad , Factor de Transcripción PAX2/análisis , Factor de Transcripción PAX2/metabolismo , Biomarcadores de Tumor/análisis , Persona de Mediana Edad , Reproducibilidad de los Resultados , Anciano , Adulto , Estudios Retrospectivos , Prevalencia , Inmunohistoquímica , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Diagnóstico Diferencial , Variaciones Dependientes del Observador , Anciano de 80 o más Años , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/mortalidadRESUMEN
We examined associations between modifiable and non-modifiable cancer-related risk factors measured at endometrial cancer diagnosis and during early survivorship (~3 years post-diagnosis) with second primary cancer (SPC) risk among 533 endometrial cancer survivors in the Alberta Endometrial Cancer Cohort using Fine and Gray sub-distribution hazard models. During a median follow-up of 16.7 years (interquartile range (IQR)=12.2-17.9), 89 (17%) participants developed a SPC with breast (29%), colorectal (13%) and lung (12%) cancers being the most common. Dietary glycemic load before endometrial cancer diagnosis (≥90.4 vs. <90.4 g/day: sub-hazard ratios (sHR)=1.71, 95% confidence intervals (CI)=1.09-2.69) as well as older age (≥60 vs. <60: sHR=2.48, 95% CI=1.34-4.62) and alcohol intake (≥2 drink/week vs. none: sHR=3.81, 95% CI=1.55-9.31) during early survivorship were associated with increased SPC risk. Additionally, reductions in alcohol consumption from prediagnosis to early survivorship significantly reduced SPC risk (sHR=0.34, 95% CI=0.14-0.82). With one-in-six survivors developing a SPC, further investigation of SPC risk factors and targeted surveillance options for high-risk survivors could improve long-term health outcomes in this population. Reductions in dietary glycemic load and alcohol intake from prediagnosis to early survivorship showed promising risk reductions for SPCs and could be important modifiable risk factors to target among endometrial cancer survivors.
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RATIONALE: Early natural menopause (early-M; <45 years of age) increases the risk of lung morbidities and mortalities in smokers. However, it is largely unknown whether early-M due to surgery demonstrates similar effects and whether menopausal hormone therapy (MHT) is protective against lung diseases. OBJECTIVES: To assess the associations of early-M and MHT with lung morbidities and mortalities using the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) trial. METHODS: We estimated the risk among 69 706 postmenopausal women in the PLCO trial, stratified by menopausal types and smoking status. RESULTS: Early-M was associated with an increased risk of most lung disease and mortality outcomes in ever smokers with the highest risk seen for respiratory mortality (HR 1.98, 95% CI 1.34 to 2.92) in those with bilateral oophorectomy (BO). Early-M was positively associated with chronic bronchitis, and all-cause, non-cancer and respiratory mortality in never smokers with natural menopause or BO, with the highest risk seen for BO- respiratory mortality (HR 1.91, 95% CI 1.16 to 3.12). Ever MHT was associated with reduced all-cause, non-cancer and cardiovascular mortality across menopause types regardless of smoking status and was additionally associated with reduced risk of non-ovarian cancer, lung cancer (LC) and respiratory mortality in ever smokers. Among smokers, ever MHT use was associated with a reduction in HR for all-cause, non-cancer and cardiovascular mortality in a duration-dependent manner. CONCLUSIONS: Smokers with early-M should be targeted for smoking cessation and LC screening regardless of menopause types. MHT users had a lower likelihood of dying from LC and respiratory diseases in ever smokers.
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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.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias Ováricas , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario/genética , Transcriptoma , Factores de Riesgo , Genómica/métodos , Estudios de Casos y Controles , MultiómicaRESUMEN
Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.
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Carcinoma Epitelial de Ovario , Nativos de Hawái y Otras Islas del Pacífico , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/etnología , Neoplasias Ováricas/epidemiología , Persona de Mediana Edad , Carcinoma Epitelial de Ovario/etnología , Carcinoma Epitelial de Ovario/epidemiología , Factores de Riesgo , Adulto , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Estudios de Casos y Controles , Anciano , Esterilización Tubaria/estadística & datos numéricos , Paridad , Asiático/estadística & datos numéricos , Población Blanca/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Estados Unidos/epidemiología , Anticonceptivos Orales/efectos adversos , Modelos Logísticos , Fumar/etnología , Fumar/epidemiología , Neoplasias Glandulares y Epiteliales/etnología , Neoplasias Glandulares y Epiteliales/epidemiología , Etnicidad/estadística & datos numéricos , Oportunidad RelativaRESUMEN
Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.
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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.
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Neoplasias Endometriales , Hipertensión , Humanos , Femenino , Neoplasias Endometriales/epidemiología , Factores de Riesgo , Hipertensión/epidemiología , Persona de Mediana Edad , Estudios de Casos y Controles , Anciano , Adulto , IncidenciaRESUMEN
PURPOSE: To examine the independent and joint relationships between cigarette smoking and alcohol consumption with survival outcomes after endometrial cancer diagnosis. METHODS: Pre- and post-diagnosis smoking and drinking histories were obtained from endometrial cancer survivors diagnosed between 2002 and 2006 during in-person interviews at-diagnosis and at ~ 3 years post-diagnosis. Participants were followed until death or January 2022. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards regression for associations with disease-free survival (DFS) and overall survival (OS). RESULTS: During a median 16.9 years of follow-up (IQR = 15.5-18.1 years), 152 of the 540 participants had a DFS event (recurrence: n = 73; deaths: n = 79) and 134 died overall. Most participants in this cohort were current drinkers (pre = 61.3%; post = 64.7%) while few were current cigarette smokers (pre = 12.8%; post = 11.5%). Pre-diagnosis alcohol consumption was not associated with survival, yet post-diagnosis alcohol intake ≥ 2 drinks/week was associated with worse OS compared with lifetime abstention (HR = 2.36, 95%CI = 1.00-5.54) as well as light intake (HR = 3.87, 95% CI = 1.67-8.96). Increased/consistently high alcohol intake patterns were associated with worse OS (HR = 2.91, 95% CI = 1.15-7.37) compared with patterns of decreased/ceased intake patterns after diagnosis. A harmful dose-response relationship per each additional pre-diagnosis smoking pack-year with OS was noted among ever smokers. In this cohort, smoking and alcohol individually were not associated with DFS and combined pre-diagnosis smoking and alcohol intakes were not associated with either outcome. CONCLUSION: Endometrial cancer survivors with higher alcohol intakes after diagnosis had poorer OS compared with women who had limited exposure. Larger studies powered to investigate the individual and joint impacts of cigarette smoking and alcohol use patterns are warranted to provide additional clarity on these modifiable prognostic factors.
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Fumar Cigarrillos , Neoplasias Endometriales , Humanos , Femenino , Estudios de Cohortes , Estudios Prospectivos , Fumar Cigarrillos/efectos adversos , Fumar Cigarrillos/epidemiología , Alberta/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Modelos de Riesgos Proporcionales , Encuestas y Cuestionarios , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/epidemiología , Factores de RiesgoRESUMEN
Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers. SIGNIFICANCE: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.
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Neoplasias de la Mama , Neoplasias de los Genitales Femeninos , Humanos , Femenino , Ligandos , Proteínas Quinasas Activadas por AMP/metabolismo , Neoplasias de los Genitales Femeninos/genética , Transducción de Señal , Neoplasias de la Mama/genética , Proteína Wnt4/genética , Carbonil Reductasa (NADPH)/metabolismoRESUMEN
OBJECTIVE: Inhibition of the MAPK pathway by MEK inhibitors (MEKi) is currently a therapeutic standard in several cancer types, including ovarian low-grade serous carcinoma (LGSC). A common MAPK pathway alteration in tubo-ovarian high-grade serous carcinoma (HGSC) is the genomic inactivation of neurofibromin 1 (NF1). The primary objectives of our study were to survey the prevalence of NF1 inactivation in the principal ovarian carcinoma histotype as well as to evaluate its associations with clinico-pathological parameters and key biomarkers including BRCA1/2 status in HGSC. METHODS: A recently commercialized NF1 antibody (clone NFC) was orthogonally validated on an automated immunohistochemistry (IHC) platform and IHC was performed on tissue microarrays containing 2140 ovarian carcinoma cases. Expression was interpreted as loss/inactivated (complete or subclonal) versus normal/retained. RESULTS: Loss of NF1 expression was detected in 250/1429 (17.4%) HGSC including 11% with subclonal loss. Survival of NF1-inactivated HGSC patients was intermediate between favorable BRCA1/2 mutated HGSC and unfavorable CCNE1 high-level amplified HGSC. NF1 inactivation was mutually exclusive with CCNE1 high-level amplifications, co-occurred with RB1 loss and occurred at similar frequencies in BRCA1/2 mutated versus wild-type HGSC. NF1 loss was found in 21/286 (7.3%) endometrioid carcinomas with a favorable prognostic association (p = 0.048), and in 4/64 (5.9%) LGSC, mutually exclusive with other driver events. CONCLUSIONS: NF1 inactivation occurs in a significant subset of BRCA1/2 wild-type HGSC and a subset of LGSC. While the functional effects of NF1 inactivation need to be further characterized, this signifies a potential therapeutic opportunity to explore targeting NF1 inactivation in these tumors.
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Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1 , Neurofibromina 1/genética , Inmunohistoquímica , Proteína BRCA2 , Neoplasias Ováricas/patología , Carcinoma Endometrioide/patología , Cistadenocarcinoma Seroso/patología , Carcinoma Epitelial de OvarioRESUMEN
BACKGROUND: Research suggests pets foster affection, connection, and physical activity, yet has failed to address the challenges people diagnosed with cancer face in caring for their pets. The objective of this study was to better understand how pets serve as emotional buffers and/or stressors for people diagnosed with breast cancer, and how their ability to meet their pet's needs affects their well-being. METHODS: A cross-section study of people diagnosed with breast cancer in the United States was conducted. Adults diagnosed with stages 0 (in situ) -IV breast cancer and currently the primary guardian of at least one dog or cat and owned the animal(s) for at least 6 months, were recruited for the study. A total of 211 responses, obtained between July - November 2022 were analyzed. The survey included questions about participants' demographics; attachment to their pets; physical, emotional, and functional well-being; social support received from their pet; and 'pet parenting' concerns. Descriptive statistics were calculated to describe participants' demographics. Multiple regression analyses were conducted to determine predictors of pet attachment, well-being, support from pet, and 'pet parenting' concerns. RESULTS: People diagnosed with breast cancer derive substantial support from their pets (80% feel their pet makes them feel loved, needed, and offers a positive presence in the home), yet only 50% of participants feel this relationship is supported by their medical team. Controlling for owner demographics, heightened levels of pet-related guilt and concerns, along with lower perceived support from their pet, are all significant predictors of a lower quality of life. CONCLUSIONS: Findings highlight the benefits pets offer people diagnosed with breast cancer, yet also the distress they feel in trying to meet their pet's needs. Assessment conversations about pet ownership, including pet-related support systems, are needed to validate people's concerns and support the identification and development of pet support teams. Medical team facilitated discussions about pet care needs is suggested to demonstrate support for the pet-parent bond and help normalize feelings of guilt related to challenges in meeting their pet's needs. These discussions could be aided through the development of research-driven intervention strategies and online, freely accessible targeted tools.
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Neoplasias de la Mama , Adulto , Humanos , Animales , Perros , Femenino , Neoplasias de la Mama/terapia , Calidad de Vida , Apoyo Social , Emociones , Encuestas y CuestionariosRESUMEN
INTRODUCTION: This study investigated the association of Vitamin D with tumor characteristics in pre and postmenopausal women. PATIENTS AND METHODS: A prospective cohort of 476 women with incident stage I-III breast cancer (BC) in Alberta, Canada comprised the study population. Vitamin D was measured as 25(OH)D concentration in serum samples collected at diagnosis (presurgery and prior to treatment initiation). Tumor characteristics including size, grade, receptor status, stage and nodal status were evaluated in regression models for association with Vitamin D and measured cytokines in models adjusted for menopausal status. RESULTS: More than half of the women were diagnosed as stage I and Luminal A/B, most were postmenopausal, had sufficient Vitamin D levels, and were 56.6 years of age on average. Higher vitamin D levels were associated with decreased tumor size for all women with larger effect seen in premenopausal status. Insufficient vitamin D levels were significantly associated with increased risk of higher grade, but only in premenopausal women. Elevated human granulocyte macrophage colony-stimulating factor was an independent risk factor associated with increased risk of higher-grade tumors. CONCLUSION: Women with sufficient Vitamin D levels at BC diagnosis had smaller and lower grade tumors compared to women with insufficient vitamin D, especially among premenopausal women. Maintaining adequate vitamin D levels in premenopausal women could improve prognostically important BC characteristics at diagnosis.
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Neoplasias de la Mama , Deficiencia de Vitamina D , Humanos , Femenino , Neoplasias de la Mama/patología , Estudios Prospectivos , Vitamina D , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , Vitaminas , Alberta/epidemiologíaRESUMEN
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.
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Neoplasias Endometriales , Ácidos Grasos Omega-3 , Humanos , Femenino , Estudios Prospectivos , Sobrepeso , Dieta , Obesidad/epidemiología , Obesidad/complicaciones , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/prevención & control , Neoplasias Endometriales/etiología , Modelos Logísticos , Factores de RiesgoRESUMEN
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.
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Neoplasias Ováricas , Embarazo , Humanos , Femenino , Carcinoma Epitelial de Ovario/epidemiología , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/etiología , Neoplasias Ováricas/patología , Factores de Riesgo , Paridad , Anticonceptivos Orales/efectos adversos , Estudios de Casos y ControlesRESUMEN
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.
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Neoplasias Endometriales , Neoplasias Ováricas , Masculino , Humanos , Femenino , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/genética , Factores de Riesgo , Curva ROC , Neoplasias Ováricas/epidemiología , IncidenciaRESUMEN
BACKGROUND: The prognostic relationship between diet and endometrial cancer survival remains largely unknown. We sought to determine pre- and post-diagnosis dietary composition, glycemic load (GL), inflammatory potential (dietary inflammatory index) and quality [Canadian Healthy Eating Index (C-HEI) 2005] associations with disease-free (DFS) and overall survival (OS) among endometrial cancer survivors. In addition, we assessed associations between dietary changes with OS and explored obesity/physical activity effect modification. METHODS: Survivors, diagnosed in Alberta, Canada between 2002 and 2006, completed past-year, food-frequency questionnaires at-diagnosis (n = 503) and 3-year follow-up (n = 395). Participants were followed to death or January 2022. Cox proportional regression estimated HR [95% confidence intervals (CI)] for dietary survival associations. RESULTS: During 16.9 median years of follow-up, 138 participants had a DFS event and 120 died. Lower pre-diagnosis GL (HRT1vsT3, 0.49; 95% CI, 0.25-0.97) and greater post-diagnosis energy intakes (EI) from total- and monounsaturated-fat (HRT3vsT1, 0.48; 95% CI, 0.26-0.87) were associated with better OS. Higher pre-diagnosis C-HEI, less inflammatory diets and lower added sugar intakes were nonlinearly associated with better DFS. Consistently low pre- to post-diagnosis EI from carbohydrates and total-fats were associated with better (HR, 0.36; 95% CI, 0.18-0.72) and worse (HR, 2.26; 95% CI, 1.21-4.20) OS, respectively. Decreased pre- to post-diagnosis C-HEI was associated with worse OS. In stratified analysis, healthy diets were most beneficial for survivors with obesity and physical inactivity. CONCLUSIONS: Adherence to higher quality dietary patterns were associated with better survival. IMPACT: Our study provides novel evidence that both pre- and post-diagnosis diet are important prognostic factors for endometrial cancer survivors. Post-diagnosis survival associations with diet composition and quality highlight the potential for future interventions.
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Dieta , Neoplasias Endometriales , Femenino , Humanos , Estudios de Cohortes , Alberta/epidemiología , Estudios Prospectivos , Neoplasias Endometriales/diagnóstico , ObesidadRESUMEN
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
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Antígeno B7-H1 , Neoplasias Ováricas , Humanos , Femenino , Antígeno B7-H1/genética , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead/uso terapéutico , Linfocitos Infiltrantes de Tumor , Microambiente TumoralRESUMEN
BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Factores de Transcripción/genética , ARN Mensajero , Cistadenocarcinoma Seroso/genética , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/uso terapéutico , Ciclina E/genéticaRESUMEN
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 13â071 EOC cases and 17â306 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.
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Estudio de Asociación del Genoma Completo , Neoplasias Ováricas , Femenino , Humanos , Carcinoma Epitelial de Ovario/genética , Alelos , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies. OBJECTIVE: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers. STUDY DESIGN: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis. RESULTS: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause. CONCLUSION: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.