Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 121
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33616777

RESUMO

OBJECTIVE: To examine the association between (GWG) and epithelial ovarian cancer (EOC). METHODS: We compared GWG between 670 incident EOC cases and 1,551 community controls from a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with GWG adjusting for potential confounders. To explore the potential effect of maternal long-term weight retention after childbearing, we restricted analyses to women who began their childbearing years as normal/underweight and examined differences in EOC risk between those who were normal/underweight versus those who were overweight/obese at study baseline reference date. RESULTS: Average GWG per full-term pregnancy did not differ between cases and controls. Among women who were normal/underweight at study baseline, greater average GWG was not associated with EOC (OR = 0.9, 0.8, 0.7 for quartiles 2, 3 and 4 of GWG gain, respectively, compared to quartile 1). In contrast, among women who were overweight/obese at study baseline, greater average GWG was positively associated with EOC (OR = 1.4, 1.8, 1.2, for quartiles 2, 3, and 4 compared to quartile 1; interaction p = 0.04). CONCLUSION: We posit that maternal post-partum weight retention and not gestational weight gain itself among normal/underweight women may impact subsequent risk of EOC. If our hypothesis is supported in other studies designed to assess this question directly, then counseling women on the importance of healthy weight management after a pregnancy could provide another means to help women reduce their risk of this often-fatal malignancy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33619020

RESUMO

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 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 overall (OR=0.65, 95% CI 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 which have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

3.
Int J Gynecol Pathol ; 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32897953

RESUMO

The chemotherapy response score (CRS) proposed by Bohm and colleagues in 2015 has been validated as a reproducible method for determining histopathologic response of tubo-ovarian carcinoma to neoadjuvant chemotherapy and stratifies tumor response into 3 groups: CRS1 is defined as minimal/no response, CRS2 as moderate response, and CRS3 as marked response. Although described as a 3-tiered system, it essentially works as a 2-tiered system (CRS1/CRS2 vs. CRS3) for assessing prognosis. Here, we analyzed the prognostic value of CRS in a large cohort of tubo-ovarian carcinomas at a tertiary care center and evaluated the potential for Ki-67 labeling index on post-neoadjuvant chemotherapy samples to provide additional prognostic information. We included 170 patients with tubo-ovarian carcinoma treated with neoadjuvant chemotherapy followed by interval debulking surgery. We determined CRS for each case by reviewing slides from the interval debulking surgery resection specimen and calculated progression-free survival and overall survival. For each case with residual disease (CRS1 and CRS2, n=123, 72%), we also performed Ki-67 antibody staining and determined both average and highest Ki-67 labeling index. Consistent with prior studies, patients in our cohort with CRS1 and CRS2 showed significantly shorter progression-free survival and overall survival compared with CRS3. Further, in the subset of cases with CRS1 and CRS2, Ki-67 labeling index was predictive of OS at multiple cutoff points. An average Ki-67 labeling index of 20% (log rank test P-value: 0.0004) or a highest Ki-67 labeling index of 50% (log rank test P-value: 0.0002) could provide a practically useful cutoff. Multivariable cox proportional hazard model showed worse overall survival with both, average Ki-67 >20% (hazard ratios: 2.02, P-value: 0.00422, confidence interval: 1.25-3.28) and highest Ki-67 >50% (hazard ratios: 1.88, P-value: 0.0205, confidence interval: 1.1-3.2). We propose adding Ki-67 labeling index to CRS to provide additional prognostic separation between patients with CRS1 and CRS2.

4.
Eur J Epidemiol ; 35(11): 1025-1042, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959149

RESUMO

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.

5.
Am J Reprod Immunol ; : e13343, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32905653

RESUMO

PROBLEM: Previous studies identified circulating CD14+ HLA-DRlo/- monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre- and post-frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy. METHOD OF STUDY: Incident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33+ CD11b+ HLA-DR-/low CD14+ CD15- monocytic cells, henceforth termed CD14+ HLA-DRlo/- monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14+ HLA-DRlo/- monocytic cell percentages and disease stage. Wilcoxon signed-rank tests evaluated changes in these monocytic cell levels pre- and post-chemotherapy in a patient subset (n = 70). RESULTS: Patients with elevated frequencies of circulating CD14+ HLA-DRlo/- monocytic cells at diagnosis were at 3.33-fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04-10.64), with a significant trend in increasing CD14+ HLA-DRlo/- monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post-chemotherapy among a subset of patients with advanced stage disease (P < .0001). CONCLUSION: These findings support the potential clinical relevance of CD14+ HLA-DRlo/- monocytic cells in EOC for prognosis and may indicate a non-invasive biomarker to measure disease progression.

6.
J Natl Cancer Inst ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32766851

RESUMO

BACKGROUND: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. METHODS: A pooled analysis of 10,470 invasive epithelial ovarian cancer cases and 16,942 controls was conducted. Odds ratios and 95% confidence intervals for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race/ethnicity, age, and education level, and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. RESULTS: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (two-sided Ptrend <.001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. CONCLUSIONS: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

7.
Gynecol Oncol ; 158(3): 702-709, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32641237

RESUMO

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

8.
J Med Genet ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546565

RESUMO

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

9.
Br J Cancer ; 123(5): 793-802, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32555365

RESUMO

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

10.
JCI Insight ; 5(11)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32369446

RESUMO

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.

11.
JAMA Oncol ; 6(6): e200421, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239218

RESUMO

Importance: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. Design, Setting, and Participants: A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. Exposures: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. Main Outcomes and Measures: Diagnosis of epithelial ovarian cancer. Results: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02). Conclusions and Relevance: Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

12.
Epidemiology ; 31(3): 402-408, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32028322

RESUMO

BACKGROUND: Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. METHODS: We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. RESULTS: Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2). CONCLUSIONS: Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.

13.
Cancer Epidemiol Biomarkers Prev ; 29(3): 599-605, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932411

RESUMO

BACKGROUND: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). METHODS: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. RESULTS: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER- tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER- disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. CONCLUSIONS: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. IMPACT: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.

14.
Int J Cancer ; 146(11): 2987-2998, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

15.
Cancer Epidemiol ; 64: 101646, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31835157

RESUMO

OBJECTIVE: To examine the association between gender of offspring and epithelial ovarian cancer (EOC). METHODS: We compared gender of offspring between 664 incident EOC cases and 1531 controls participating in a population-based study conducted in Pennsylvania, Ohio, and New York from 2003-2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) adjusting for potential confounders. RESULTS: Bearing a male offspring was associated with an 8 % lower EOC risk; bearing all boys was associated with an 11 % lower risk. Compared to bearing all girls, bearing all boys was associated with a 14 % decrease risk. Increasing number of male offspring increased the protective effect (adjusted-OR: 0.92, 0.91, 0.84, for 1, 2, and 3+ boys compared to all girls). Results where similar when limiting cases to invasive disease and to the high-grade serous histotype. CONCLUSION: Fetal sex, which influences maternal hormonal milieu, may impact EOC risk.


Assuntos
Neoplasias Ovarianas/etiologia , Idoso , Estudos de Casos e Controles , Feminino , Identidade de Gênero , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fatores de Risco
16.
Cancer Biomark ; 26(4): 471-479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658047

RESUMO

Ovarian cancer is the leading cause of death among gynecologic diseases in the USA and Europe. High-grade serous carcinoma (HGSC) of the ovary, the most aggressive type of ovarian cancer, is typically diagnosed at advanced stages when the 5-year survival is dismal. Since the cure rate for stage I HGSC is high, early detection of localized initial disease may improve patient outcomes. Serous tubal intraepithelial carcinoma (STIC) is considered to be a precursor lesion of HGSC. Discovery of biomarkers associated with STIC could aid in the development of an HGSC screening algorithm. Using immunohistochemical staining, we have demonstrated overexpression of UCHL1, ADAMTS13, and GAPDH in patients' STIC lesions, but not in cancer-free fallopian tubes. We additionally demonstrated a marked increase of T cells in perineoplastic stroma surrounding STIC lesions (largely CD4 + cells), but not in normal fallopian tubes and HGSC. FOXP3 + T regulatory cells are absent in STIC lesions but are present in HGSC. These observations indicate the microenvironment surrounding a STIC lesion may be immune promoting in contrast to the immune suppressive microenvironment of invasive carcinoma. In summary, we have identified UCHL1, ADAMTS13, and GAPDH as novel potentially useful markers associated with early stages of HGSC tumorigenesis and possibly contribute to STIC immunogenicity. The lack of immune suppression in the STIC microenvironment indicates that the immune system can still recognize and keep STIC controlled at this stage of the tumor development.


Assuntos
Carcinoma in Situ/imunologia , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/imunologia , Carcinogênese , Carcinoma in Situ/patologia , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia
17.
Mod Pathol ; 32(12): 1834-1846, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31239549

RESUMO

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/análise , Queratina-7/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/análise , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica/diagnóstico , Sensibilidade e Especificidade
18.
Int J Epidemiol ; 48(3): 822-830, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211375

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.


Assuntos
Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma Mucinoso/epidemiologia , Carcinoma Endometrioide/epidemiologia , Neoplasias Ovarianas/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Feminino , Humanos , Análise da Randomização Mendeliana , Neoplasias Císticas, Mucinosas e Serosas/epidemiologia , Síndrome do Ovário Policístico/genética
19.
Cancer Med ; 8(5): 2503-2513, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.


Assuntos
Afro-Americanos/genética , Carcinoma Epitelial do Ovário/genética , Glucuronosiltransferase/genética , Neoplasias Ovarianas/genética , Receptores de Calcitriol/genética , Teorema de Bayes , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Receptores ErbB/genética , Feminino , Estudos de Associação Genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Vitamina D/biossíntese
20.
Cancer Causes Control ; 30(5): 537-547, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30905014

RESUMO

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.


Assuntos
Carcinoma Epitelial do Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Comportamento Sedentário , Fumar/epidemiologia , Feminino , Humanos , Atividade Motora , Obesidade/complicações , Neoplasias Ovarianas/mortalidade , Sobrepeso/complicações , Modelos de Riscos Proporcionais , Fatores de Risco , Fumar/efeitos adversos , Ganho de Peso
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA