Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 191
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33723363

RESUMO

BACKGROUND: Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. METHODS: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. RESULTS: Median age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p < 10-15). CONCLUSIONS: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.

2.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623038

RESUMO

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.


Assuntos
Grupos Étnicos/genética , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Autorrelato
4.
Nat Genet ; 53(1): 65-75, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398198

RESUMO

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Invasividade Neoplásica , Razão de Chances , Neoplasias da Próstata/diagnóstico , Fatores de Risco
5.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

6.
Eur Urol Oncol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33436325

RESUMO

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

7.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

8.
Ann Rheum Dis ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33229363

RESUMO

OBJECTIVES: To evaluate the risk of association with hip osteoarthritis (OA) of 14 morphological features measured on standard antero-posterior pelvis radiographs. METHODS: A case-control study of 566 symptomatic unilateral hip OA cases and 1108 controls without hip OA, using the Genetics of OA and Lifestyle database. Unaffected hips of cases were assumed to reflect pre-OA morphology of the contralateral affected hip. ORs with 95% CI adjusted for confounding factors were calculated using logistic regression. Hierarchical clustering on principal component method was used to identify clusters of morphological features. Proportional risk contribution (PRC) of these morphological features in the context of other risk factors of hip OA was estimated using receiver operating characteristic analysis. RESULTS: All morphological features showed right-left symmetry in controls. Each feature was associated with hip OA after adjusting for age, gender and body mass index. Increased sourcil angle had the strongest association (OR: 6.93, 95% CI 5.16 to 9.32). Three clusters were identified. The PRC varied between individual features, as well as between clusters. It was 35% (95% CI 31% to 40%) for all 14 morphological features, compared to 21% (95% CI 19% to 24%) for all other well-established risk factors. CONCLUSIONS: Constitutional morphological variation strongly associates with hip OA development and may explain much of its heritability. Relevant morphological measures can be assessed readily on standard radiographs to help predict risk of hip OA. Prospective studies are required to provide further support for causality.

9.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158149

RESUMO

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

10.
PLoS One ; 15(9): e0238928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941451

RESUMO

INTRODUCTION: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate. OBJECTIVE: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape. METHODS: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored. RESULTS: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92). CONCLUSIONS: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations.


Assuntos
Tamanho Corporal , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Autorrelato , Reino Unido/epidemiologia
11.
Nat Commun ; 11(1): 3833, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737321

RESUMO

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Ásia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Risco
12.
BMJ Open ; 10(7): e034661, 2020 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-32690501

RESUMO

OBJECTIVE: To identify risk prediction models for prostate cancer (PCa) that can be used in the primary care and community health settings. DESIGN: Systematic review. DATA SOURCES: MEDLINE and Embase databases combined from inception and up to the end of January 2019. ELIGIBILITY: Studies were included based on satisfying all the following criteria: (i) presenting an evaluation of PCa risk at initial biopsy in patients with no history of PCa, (ii) studies not incorporating an invasive clinical assessment or expensive biomarker/genetic tests, (iii) inclusion of at least two variables with prostate-specific antigen (PSA) being one of them, and (iv) studies reporting a measure of predictive performance. The quality of the studies and risk of bias was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). DATA EXTRACTION AND SYNTHESIS: Relevant information extracted for each model included: the year of publication, source of data, type of model, number of patients, country, age, PSA range, mean/median PSA, other variables included in the model, number of biopsy cores to assess outcomes, study endpoint(s), cancer detection, model validation and model performance. RESULTS: An initial search yielded 109 potential studies, of which five met the set criteria. Four studies were cohort-based and one was a case-control study. PCa detection rate was between 20.6% and 55.8%. Area under the curve (AUC) was reported in four studies and ranged from 0.65 to 0.75. All models showed significant improvement in predicting PCa compared with being based on PSA alone. The difference in AUC between extended models and PSA alone was between 0.06 and 0.21. CONCLUSION: Only a few PCa risk prediction models have the potential to be readily used in the primary healthcare or community health setting. Further studies are needed to investigate other potential variables that could be integrated into models to improve their clinical utility for PCa testing in a community setting.

13.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

14.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

15.
JAMA Netw Open ; 3(4): e203760, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32329772

RESUMO

Importance: The association between noninherited factors, including lifestyle factors, and the risk of breast cancer (BC) in women and the association between BC and genetic makeup are only partly characterized. A study using data on current genetic stratification may help in the characterization. Objective: To examine the association between healthier lifestyle habits and BC risk in genetically predisposed groups. Design, Setting, and Participants: Data from UK Biobank, a prospective cohort comprising 2728 patients with BC and 88 489 women without BC, were analyzed. The data set used for the analysis was closed on March 31, 2019. The analysis was restricted to postmenopausal white women. Classification of healthy lifestyle was based on Cancer Research UK guidance (healthy weight, regular exercise, no use of hormone replacement therapy for more than 5 years, no oral contraceptive use, and alcohol intake <3 times/wk). Three groups were established: favorable (≥4 healthy factors), intermediate (2-3 healthy factors), and unfavorable (≤1 healthy factor). The genetic contribution was estimated using the polygenic risk scores of 305 preselected single-nucleotide variations. Polygenic risk scores were categorized into 3 tertiles (low, intermediate, and high). Main Outcomes and Measures: Cox proportional hazards regression was used to assess the hazard ratios (HRs) of the lifestyles and polygenic risk scores associated with a malignant neoplasm of the breast. Results: Mean (SD) age of the 2728 women with BC was 60.1 (5.5) years, and mean age of the 88 489 women serving as controls was 59.4 (4.9) years. The median follow-up time for the cohort was 10 years (maximum 13 years) (interquartile range, 9.44-10.82 years). Women with BC had a higher body mass index (relative risk [RR], 1.14; 95% CI, 1.05-1.23), performed less exercise (RR, 1.12; 95% CI, 1.01-1.25), used hormonal replacement therapy for longer than 5 years (RR, 1.23; 95% CI, 1.13-1.34), used more oral contraceptives (RR, 1.02; 95% CI, 0.93-1.12), and had greater alcohol intake (RR, 1.11; 95% CI, 1.03-1.19) compared with the controls. Overall, 20 657 women (23.3%) followed a favorable lifestyle, 60 195 women (68.0%) followed an intermediate lifestyle, and 7637 women (8.6%) followed an unfavorable lifestyle. The RR of the highest genetic risk group was 2.55 (95% CI, 2.28-2.84), and the RR of the most unfavorable lifestyle category was 1.44 (95% CI, 1.25-1.65). The association of lifestyle and BC within genetic subgroups showed lower HRs among women following a favorable lifestyle compared with intermediate and unfavorable lifestyles among all of the genetic groups: women with an unfavorable lifestyle had a higher risk of BC in the low genetic group (HR, 1.63; 95% CI, 1.13-2.34), intermediate genetic group (HR, 1.94; 95% CI, 1.46-2.58), and high genetic group (HR, 1.39; 95% CI, 1.11-1.74) compared with the reference group of favorable lifestyle. Intermediate lifestyle was also associated with a higher risk of BC among the low genetic group (HR, 1.40; 95% CI, 1.09-1.80) and the intermediate genetic group (HR, 1.37; 95% CI, 1.12-1.68). Conclusions and Relevance: In this cohort study of data on women in the UK Biobank, a healthier lifestyle with more exercise, healthy weight, low alcohol intake, no oral contraceptive use, and no or limited hormonal replacement therapy use appeared to be associated with a reduced level of risk for BC, even if the women were at higher genetic risk for BC.


Assuntos
Neoplasias da Mama/epidemiologia , Estilo de Vida Saudável/classificação , Idoso , Bancos de Espécimes Biológicos , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia
16.
Nat Commun ; 11(1): 1217, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139696

RESUMO

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Predisposição Genética para Doença , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Receptores Estrogênicos/metabolismo , Fatores de Risco
17.
Int J Cancer ; 146(8): 2130-2138, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265136

RESUMO

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Locos de Características Quantitativas
18.
J Natl Cancer Inst ; 112(3): 295-304, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31143935

RESUMO

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Ilhas de CpG , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Risco , Transcriptoma
19.
EBioMedicine ; 48: 203-211, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31629678

RESUMO

BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. INTERPRETATION: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.


Assuntos
Grupo com Ancestrais do Continente Asiático , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Variação Genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Caspase 8 , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Risco
20.
PLoS Med ; 16(8): e1002893, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31390370

RESUMO

BACKGROUND: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. METHODS AND FINDINGS: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. CONCLUSIONS: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/etiologia , Neoplasias Ovarianas/etiologia , Fatores Etários , Índice de Massa Corporal , Carcinoma Epitelial do Ovário/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Menarca , Análise da Randomização Mendeliana , Menopausa , Neoplasias Ovarianas/genética , Paridade , Fatores de Risco , Fumar/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...