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1.
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.

2.
Arch Pathol Lab Med ; 145(2): 222-226, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33501497

RESUMO

CONTEXT.­: The Surveillance, Epidemiology, and End Results (SEER) cancer registry program is currently evaluating the use of archival, diagnostic, formalin-fixed, paraffin-embedded (FFPE) tissue obtained through SEER cancer registries, functioning as honest brokers for deidentified tissue and associated data. To determine the feasibility of this potential program, laboratory policies for sharing tissue for research needed to be assessed. OBJECTIVE.­: To understand the willingness of pathology laboratories to share archival diagnostic tissue for cancer research and related policies. DESIGN.­: Seven SEER registries administered a 27-item questionnaire to pathology laboratories within their respective registry catchment areas. Only laboratories that processed diagnostic FFPE specimens and completed the questionnaire were included in the analysis. RESULTS.­: Of the 153 responding laboratories, 127 (83%) responded that they process FFPE specimens. Most (n = 88; 69%) were willing to share tissue specimens for research, which was not associated with the number of blocks processed per year by the laboratories. Most laboratories retained the specimens for at least 10 years. Institutional regulatory policies on sharing deidentified tissue varied considerably, ranging from requiring a full Institutional Review Board review to considering such use exempt from Institutional Review Board review, and 43% (55 of 127) of the laboratories did not know their terms for sharing tissue for research. CONCLUSIONS.­: This project indicated a general willingness of pathology laboratories to participate in research by sharing FFPE tissue. Given the variability of research policies across laboratories, it is critical for each SEER registry to work with laboratories in their catchment area to understand such policies and state legislation regulating tissue retention and guardianship.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33144283

RESUMO

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel sub-genome wide regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation. CONCLUSION: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

4.
Int J Cancer ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33105052

RESUMO

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

5.
CBE Life Sci Educ ; 19(3): es11, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32870086

RESUMO

Recent calls in biology education research (BER) have recommended that researchers leverage learning theories and methodologies from other disciplines to investigate the mechanisms by which students to develop sophisticated ideas. We suggest design-based research from the learning sciences is a compelling methodology for achieving this aim. Design-based research investigates the "learning ecologies" that move student thinking toward mastery. These "learning ecologies" are grounded in theories of learning, produce measurable changes in student learning, generate design principles that guide the development of instructional tools, and are enacted using extended, iterative teaching experiments. In this essay, we introduce readers to the key elements of design-based research, using our own research into student learning in undergraduate physiology as an example of design-based research in BER. Then, we discuss how design-based research can extend work already done in BER and foster interdisciplinary collaborations among cognitive and learning scientists, biology education researchers, and instructors. We also explore some of the challenges associated with this methodological approach.


Assuntos
Biologia/educação , Pesquisa/educação , Comportamento Cooperativo , Humanos , Aprendizagem , Fisiologia/educação , Estudantes
6.
BMC Cancer ; 20(1): 905, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32962699

RESUMO

BACKGROUND: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. METHODS: The ß-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation ß-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. RESULTS: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively). CONCLUSIONS: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

7.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

8.
J Biomed Inform ; 110: 103564, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32919043

RESUMO

OBJECTIVE: In machine learning, it is evident that the classification of the task performance increases if bootstrap aggregation (bagging) is applied. However, the bagging of deep neural networks takes tremendous amounts of computational resources and training time. The research question that we aimed to answer in this research is whether we could achieve higher task performance scores and accelerate the training by dividing a problem into sub-problems. MATERIALS AND METHODS: The data used in this study consist of free text from electronic cancer pathology reports. We applied bagging and partitioned data training using Multi-Task Convolutional Neural Network (MT-CNN) and Multi-Task Hierarchical Convolutional Attention Network (MT-HCAN) classifiers. We split a big problem into 20 sub-problems, resampled the training cases 2,000 times, and trained the deep learning model for each bootstrap sample and each sub-problem-thus, generating up to 40,000 models. We performed the training of many models concurrently in a high-performance computing environment at Oak Ridge National Laboratory (ORNL). RESULTS: We demonstrated that aggregation of the models improves task performance compared with the single-model approach, which is consistent with other research studies; and we demonstrated that the two proposed partitioned bagging methods achieved higher classification accuracy scores on four tasks. Notably, the improvements were significant for the extraction of cancer histology data, which had more than 500 class labels in the task; these results show that data partition may alleviate the complexity of the task. On the contrary, the methods did not achieve superior scores for the tasks of site and subsite classification. Intrinsically, since data partitioning was based on the primary cancer site, the accuracy depended on the determination of the partitions, which needs further investigation and improvement. CONCLUSION: Results in this research demonstrate that 1. The data partitioning and bagging strategy achieved higher performance scores. 2. We achieved faster training leveraged by the high-performance Summit supercomputer at ORNL.

9.
Science ; 369(6509)2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32913074

RESUMO

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.


Assuntos
Envelhecimento/genética , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Telômero/fisiologia , Marcadores Genéticos , Variação Genética , Humanos , Especificidade de Órgãos
10.
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.

11.
Mod Pathol ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724153

RESUMO

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

12.
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.

13.
Arch Pathol Lab Med ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32496836

RESUMO

CONTEXT.­: The Surveillance, Epidemiology, and End Results (SEER) cancer registry program is currently evaluating the use of archival, diagnostic, formalin-fixed, paraffin-embedded (FFPE) tissue obtained through SEER cancer registries, functioning as honest brokers for deidentified tissue and associated data. To determine the feasibility of this potential program, laboratory policies for sharing tissue for research needed to be assessed. OBJECTIVE.­: To understand the willingness of pathology laboratories to share archival diagnostic tissue for cancer research and related policies. DESIGN.­: Seven SEER registries administered a 27-item questionnaire to pathology laboratories within their respective registry catchment areas. Only laboratories that processed diagnostic FFPE specimens and completed the questionnaire were included in the analysis. RESULTS.­: Of the 153 responding laboratories, 127 (83%) responded that they process FFPE specimens. Most (n = 88; 69%) were willing to share tissue specimens for research, which was not associated with the number of blocks processed per year by the laboratories. Most laboratories retained the specimens for at least 10 years. Institutional regulatory policies on sharing deidentified tissue varied considerably, ranging from requiring a full Institutional Review Board review to considering such use exempt from Institutional Review Board review, and 43% (55 of 127) of the laboratories did not know their terms for sharing tissue for research. CONCLUSIONS.­: This project indicated a general willingness of pathology laboratories to participate in research by sharing FFPE tissue. Given the variability of research policies across laboratories, it is critical for each SEER registry to work with laboratories in their catchment area to understand such policies and state legislation regulating tissue retention and guardianship.

14.
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.

15.
Gynecol Oncol ; 157(2): 529-535, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32122688

RESUMO

OBJECTIVE: While genitourinary complications during treatment for ovarian cancer are well-known, long-term adverse outcomes have not been well characterized. The number of ovarian cancer survivors has been increasing. The aim of this study was to investigate long-term adverse genitourinary outcomes in a population-based cohort. METHODS: We identified a cohort of 1270 ovarian cancer survivors diagnosed between 1996 and 2012 from the Utah Cancer Registry, and 5286 cancer-free women were matched on birth year and state from the Utah Population Database. Genitourinary disease diagnoses were identified through ICD-9 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazards models were used to estimate hazard ratios (HR) for genitourinary outcomes at 1 to <5 years and 5+ years after ovarian cancer diagnosis. RESULTS: Ovarian cancer survivors had increased risks for urinary system disorders (HR: 2.53, 95% CI: 2.12-3.01) and genital organ disorders (HR: 1.88, 95% CI: 1.57-2.27) between 1 and <5 years after cancer diagnosis compared to the general population cohort. Increased risks were observed for acute renal failure, chronic kidney disease, calculus of kidney, hydronephrosis, pelvic peritoneal adhesions, and pelvic organ inflammatory conditions. Increased risks of several of these diseases were observed 5+ years after cancer diagnosis. CONCLUSIONS: Ovarian cancer survivors experience increased risks of various genitourinary diseases compared to women in the general population in the long-term. Understanding the multimorbidity trajectory among ovarian cancer survivors is important to improve clinical care after cancer treatment is completed.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Doenças dos Genitais Femininos/epidemiologia , Neoplasias Ovarianas/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Sistema de Registros , Utah/epidemiologia , Adulto Jovem
16.
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.

17.
Cancer Epidemiol Biomarkers Prev ; 29(4): 807-815, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32098891

RESUMO

BACKGROUND: Previously, family-based designs and high-risk pedigrees have illustrated value for the discovery of high- and intermediate-risk germline breast cancer susceptibility genes. However, genetic heterogeneity is a major obstacle hindering progress. New strategies and analytic approaches will be necessary to make further advances. One opportunity with the potential to address heterogeneity via improved characterization of disease is the growing availability of multisource databases. Specific to advances involving family-based designs are resources that include family structure, such as the Utah Population Database (UPDB). To illustrate the broad utility and potential power of multisource databases, we describe two different novel family-based approaches to reduce heterogeneity in the UPDB. METHODS: Our first approach focuses on using pedigree-informed breast tumor phenotypes in gene mapping. Our second approach focuses on the identification of families with similar pleiotropies. We use a novel network-inspired clustering technique to explore multi-cancer signatures for high-risk breast cancer families. RESULTS: Our first approach identifies a genome-wide significant breast cancer locus at 2q13 [P = 1.6 × 10-8, logarithm of the odds (LOD) equivalent 6.64]. In the region, IL1A and IL1B are of particular interest, key cytokine genes involved in inflammation. Our second approach identifies five multi-cancer risk patterns. These clusters include expected coaggregations (such as breast cancer with prostate cancer, ovarian cancer, and melanoma), and also identify novel patterns, including coaggregation with uterine, thyroid, and bladder cancers. CONCLUSIONS: Our results suggest pedigree-informed tumor phenotypes can map genes for breast cancer, and that various different cancer pleiotropies exist for high-risk breast cancer pedigrees. IMPACT: Both methods illustrate the potential for decreasing etiologic heterogeneity that large, population-based multisource databases can provide.See all articles in this CEBP Focus section, "Modernizing Population Science."

18.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
19.
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.

20.
JCO Clin Cancer Inform ; 3: 1-10, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31756128

RESUMO

PURPOSE: Incompleteness of treatment data is a recognized limitation of cancer registry data. An all-payer claims database (APCD) is a tool that states use to capture health care information across systems and payer. We linked the Utah Cancer Registry (UCR) records to Utah's statewide APCD and evaluated how this linkage led to improvements in the capture of cancer treatment information. METHODS: We linked cancers diagnosed and reported to the UCR with Utah APCD claims for the calendar years 2013 and 2014 using LinkPlus Software. For patients with breast or colorectal cancers, manual abstraction was completed to provide a gold-standard comparison for the treatment data obtained from the claims. RESULTS: Among 10,759 reportable cancer occurrences linked to the APCD, the claims identified additional patients with cancer who received therapies that had been unknown to the registry, increasing the proportion treated with chemotherapy from 23.7% to 27.6%, hormone therapy from 14.1% to 18.8%, immunotherapy from 4.3% to 13.2%, and radiation therapy from 24.9% to 27.5%. The APCD increased the sensitivity of treatment variables compared with the abstraction gold standard. Notably, sensitivity of hormonal therapy for breast cancer increased from 78.6% to 95.2% when augmented with APCD claims data. However, the APCD alone did not achieve as high specificity for treatment data as did the data collected through traditional registry methods. CONCLUSIONS: This is the first study, to our knowledge, showing that linking cancer registry data with a statewide claims database that covers multiple insurance companies improves cancer treatment data collection. Linking of cancer registry and APCD data can improve comprehensiveness of cancer registry treatment data.


Assuntos
Bases de Dados Factuais/estatística & dados numéricos , Revisão da Utilização de Seguros/estatística & dados numéricos , Neoplasias/terapia , Sistema de Registros/estatística & dados numéricos , Idoso , Coleta de Dados/métodos , Gerenciamento de Dados/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Utah/epidemiologia
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