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1.
PLoS One ; 14(6): e0218188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188874

RESUMO

BACKGROUND: Personal cancer risk assessments enable stratified care, for example, offering preventive surgical measures such as risk-reducing mastectomy (RRM) to women at high risk for breast cancer. In scenario-based experiments, we investigated whether different benefit-harm ratios of RRM influence women's consideration of this, whether this consideration is influenced by women's perception of and desire to know their personal cancer risk, or by their intention to take a novel cancer risk-predictive test, and whether consideration varies across different countries. METHOD: In January 2017, 1,675 women 40 to 75 years of age from five European countries-Czech Republic, Germany, UK, Italy, and Sweden-took part in an online scenario-based experiment. Six different scenarios of hypothetical benefit-harm ratios of RRM were presented in accessible fact box formats: Baseline risk/risk reduction pairings were 20/16, 20/4, 10/8, 10/2, 5/4, and 5/1 out of 1,000 women dying from breast cancer. RESULTS: Varying the baseline risk of dying from breast cancer and the extent of risk reduction influenced the decision to consider RRM for 23% of women. Decisions varied by country, risk perception, and the intention to take a cancer risk-predictive test. Women who expressed a stronger intention to take such a test were more likely to consider having RRM. The desire to know one's risk of developing any female cancer in general moderated women's decisions, whereas the specific desire to know the risk of breast cancer did not. CONCLUSIONS: In this hypothetical scenario-based study, only for a minority of women did the change in benefit-harm ratio inform their consideration of RRM. Because this consideration is influenced by risk perception and the intention to learn one's cancer risks via a cancer risk-predictive test, careful disclosure of different potential preventive measures and their benefit-harm ratios is necessary before testing for individual risk. Furthermore, information on risk testing should acknowledge country-specific sensitivities for benefit-harm ratios.

2.
BMC Public Health ; 19(1): 667, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146730

RESUMO

BACKGROUND: Epigenetic markers might be used for risk-stratifying cancer screening and prevention programs in the future. Although the clinical utility of consequent epigenetic tests for risk stratification is yet to be proven, successful adoption into clinical practice also requires the public's acceptance of such tests. This cross-sectional online survey study sought to learn for the first time about European women's perceptions, attitudes, and intended behavior regarding a predictive epigenetic test for female cancer (breast, ovarian, cervical, and endometrial) risks. METHODS: 1675 women (40-75 years) from five European countries (Czech Republic, Germany, United Kingdom, Italy, Sweden), drawn from online panels by the survey sampling company Harris Interactive (Germany), participated in an online survey where they first received online leaflet information on a predictive epigenetic test for female cancer risks and were subsequently queried by an online questionnaire on their desire to know their female cancer risks, their perception of the benefit-to-harm ratio of an epigenetic test predicting female cancer risks, reasons in favor and disfavor of taking such a test, and their intention to take a predictive epigenetic test for female cancer risks. RESULTS: Most women desired information on each of their female cancer risks, 56.6% (95% CI: 54.2-59.0) thought the potential benefits outweighed potential harms, and 75% (72.0-77.8) intended to take a predictive epigenetic test for female cancer risks if freely available. Results varied considerably by country with women from Germany and the Czech Republic being more reserved about this new form of testing than women from the other three European countries. The main reason cited in favor of a predictive epigenetic test for female cancer risks was its potential to guide healthcare strategies and lifestyle changes in the future, and in its disfavor was that it may increase cancer worry and coerce unintended lifestyle changes and healthcare interventions. CONCLUSIONS: A successful introduction of predictive epigenetic tests for cancer risks will require a balanced and transparent communication of the benefit-to-harm ratio of healthcare pathways resulting from such tests in order to curb unjustified expectations and at the same time to prevent unjustified concerns.


Assuntos
Detecção Precoce de Câncer/psicologia , Epigênese Genética , Testes Genéticos/métodos , Conhecimentos, Atitudes e Prática em Saúde , Intenção , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos Transversais , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Valor Preditivo dos Testes , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética
4.
Maturitas ; 122: 66-72, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797533

RESUMO

OBJECTIVES: The parent-child relationship is critical for human development, yet little is known about its association with offsprings' reproductive health outside the context of abuse and neglect. We investigated whether childhood experiences of poor-quality parenting (characterized as decreased parental care and increased parental overprotection) are associated with women's reproductive timing and lifespan. STUDY DESIGN: Observational study of 2383 women aged 55-89 years in 2007 from the English Longitudinal Study of Ageing (ELSA). Multinomial logistic regression models were estimated. MAIN OUTCOME MEASURES: Self-reported ages at menarche and menopause and duration of reproductive lifespan. RESULTS: Increasing maternal and paternal overprotection were associated with later menarche (≥16 years) after adjustment for age and childhood socioeconomic position (relative risk ratio (RRR) 1.11, 95% CI 1.02-1.21 and 1.11, 95% CI 1.01-1.21, respectively, per unit increase in the predictor). Increasing parental overprotection and decreasing paternal care were associated with earlier menarche (≤10 years). However, these associations were marginally non-significant. Maternal and paternal overprotection were also inversely associated with age at natural menopause after adjustment for age, childhood socioeconomic position and age at menarche (p value for linear trend = 0.041 and 0.004, respectively). Further, increasing paternal overprotection was associated with a shorter reproductive lifespan (≤33 years) (RRR 1.09 (1.01-1.18), per unit increase in the predictor) after adjustment for age and childhood socioeconomic position. Adjustment for additional childhood and adult factors did not explain these associations. CONCLUSIONS: Women who experienced poor-quality parenting in childhood, especially increased levels of parental overprotection, might be at increased risk of an unfavourable reproductive health profile that is characterized by late or early menarche, premature menopause and a shorter reproductive lifespan.


Assuntos
Envelhecimento , Menarca , Menopausa , Poder Familiar , Saúde Reprodutiva , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Pessoa de Meia-Idade , Razão de Chances , Reprodução , Autorrelato
8.
Nat Commun ; 10(1): 419, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664635

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

9.
Nat Commun ; 10(1): 213, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631080

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

11.
Nat Commun ; 9(1): 4616, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397198

RESUMO

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30352818

RESUMO

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

13.
Public Health Genomics ; : 1-8, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30223261

RESUMO

BACKGROUND AND OBJECTIVE: Advances in omics open new opportunities for cancer risk prediction and risk-based screening interventions. However, implementation of risk prediction in clinical practice may impact the ethical, legal, and regulatory aspects of current cancer screening programs. In order to support decision-making, we analyzed the ethical, legal, and regulatory issues and developed a set of Points to Consider to support management of these issues. METHODS: We analyzed the legal and policy frameworks applicable to breast and cervical cancer screening programs in 7 European countries. We identified the most relevant issues to be considered, and we developed considerations for their management, based on the literature, the legal and policy frameworks, and our experience with similar issues. RESULTS: The considerations focus on five topics: (A) health services planning, (B) information and invitation, (C) consent and data/sample collection, (D) risk calculation and communication of results, and (E) storage of data and residual samples. CONCLUSION: Current frameworks might not be adequate to implement a risk prediction approach using omics factors due to the different characteristics of such approaches.

14.
Blood ; 132(19): 2040-2052, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30194254

RESUMO

To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.

15.
Nat Commun ; 9(1): 3707, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213928

RESUMO

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

16.
JAMA Oncol ; 4(11): 1504-1510, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29978189

RESUMO

Importance: The age-based or "one-size-fits-all" breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk-stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources. Objective: To assess the benefit-to-harm ratio and the cost-effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening. Design, Setting, and Population: A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective. Interventions: The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017. Main Outcomes and Measures: Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year. Results: The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk-stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of £20 000 (US $26 800) per QALY gained, with a 72% probability of being cost-effective. Compared with age-based screening, risk-stratified screening at the 32nd percentile vs 70th percentile risk threshold would cost £20 066 (US $26 888) vs £537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively. Conclusions and Relevance: Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening.

17.
BMC Cancer ; 18(1): 615, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855264

RESUMO

BACKGROUND: Emergency presentations (EP) represent over a third of all lung cancer admissions in England. Such presentations usually reflect late stage disease and are associated with poor survival. General practitioners (GPs) act as gate-keepers to secondary care and so we sought to understand the association between GP practice characteristics and lung cancer EP. METHODS: Data on general practice characteristics were extracted for all practices in England from the Quality Outcomes Framework, the Health and Social Care Information Centre, the GP Patient Survey, the Cancer Commissioning Toolkit and the area deprivation score for each practice. After linking these data to lung cancer patient registrations in 2006-2013, we explored trends in three types of EP, patient-led, GP-led and 'other', by general practice characteristics and by socio-demographic characteristics of patients. RESULTS: Overall proportions of lung cancer EP decreased from 37.9% in 2006 to 34.3% in 2013. Proportions of GP-led EP nearly halved during this period, from 28.3 to 16.3%, whilst patient-led emergency presentations rose from 62.1 to 66.7%. When focusing on practice-specific levels of EP, 14% of general practices had higher than expected proportions of EP at least once in 2006-13, but there was no evidence of clustering of patients within practice, meaning that none of the practice characteristics examined explained differing proportions of EP by practice. CONCLUSION: We found that the high proportion of lung cancer EP is not the result of a few practices with very abnormal patterns of EP, but of a large number of practices susceptible to reaching high proportions of EP. This suggests a system-wide issue, rather than problems with specific practices. High proportions of lung cancer EP are mainly the result of patient-initiated attendances in A&E. Our results demonstrate that interventions to encourage patients not to bypass primary care must be system wide rather than targeted at specific practices.

18.
Bioinformatics ; 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29878078

RESUMO

Motivation: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions. Results: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies. Availability: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/. Contact: hlin1@lsuhsc.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

19.
Eur Urol ; 74(3): 248-252, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29935977

RESUMO

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.

20.
Nat Genet ; 50(7): 928-936, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29892016

RESUMO

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

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