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1.
Nat Commun ; 12(1): 1078, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597508

RESUMO

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

2.
Metabolites ; 11(2)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578791

RESUMO

Breast cancer is the most common cancer in women, but its incidence can only be partially explained through established risk factors. Our aim was to use metabolomics to identify novel risk factors for breast cancer and to validate recently reported metabolite-breast cancer findings. We measured levels of 1275 metabolites in prediagnostic serum in a nested case-control study of 782 postmenopausal breast cancer cases and 782 matched controls. Metabolomics analysis was performed by Metabolon Inc using ultra-performance liquid chromatography and a Q-Exactive high resolution/accurate mass spectrometer. Controls were matched by birth date, date of blood draw, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer at the 90th versus 10th percentile (modeled on a continuous basis) of metabolite levels were estimated using conditional logistic regression, with adjustment for age. Twenty-four metabolites were significantly associated with breast cancer risk at a false discovery rate <0.20. For the nine metabolites positively associated with risk, the ORs ranged from 1.75 (95% CI: 1.29-2.36) to 1.45 (95% CI: 1.13-1.85), and for the 15 metabolites inversely associated with risk, ORs ranged from 0.59 (95% CI: 0.43-0.79) to 0.69 (95% CI: 0.55-0.87). These metabolites largely comprised carnitines, glycerolipids, and sex steroid metabolites. Associations for three sex steroid metabolites validated findings from recent studies and the remainder were novel. These findings contribute to growing data on metabolite-breast cancer associations by confirming prior findings and identifying novel leads for future validation efforts.

3.
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
4.
N Engl J Med ; 384(5): 440-451, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471974

RESUMO

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
6.
PLoS One ; 15(9): e0237792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881892

RESUMO

BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8). CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Células Germinativas/metabolismo , Sarcoma de Ewing/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
7.
J Natl Cancer Inst ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359158

RESUMO

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

8.
Genet Epidemiol ; 44(5): 442-468, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32115800

RESUMO

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Feminino , Predisposição Genética para Doença , Genômica , Humanos , Medição de Risco , Transcriptoma , Proteínas de Transporte Vesicular/genética
9.
Obesity (Silver Spring) ; 28(1): 187-196, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777189

RESUMO

OBJECTIVE: This study was undertaken to identify metabolites associated with BMI and waist circumference (WC) in women and to determine whether these metabolites are associated with biomarkers of metabolic health. METHODS: Untargeted metabolomic analysis was done on serum from 1,534 women. Metabolites associated with BMI and WC were identified using linear regression with a Bonferroni-corrected P value. Clustered blocks of these metabolites were then defined whose association with the anthropometric measures could be represented by a single metabolite. The association of these representative metabolites with biomarkers for diabetes and inflammation was then determined. RESULTS: About one-third of 781 metabolites included in the analyses were associated with BMI and/or WC. Associations were found for some novel metabolites, including several sphingolipids, nucleotides, and modified fatty acids. Among metabolites most strongly inversely associated with BMI, the choline-containing plasmalogen (O-16:0/18:1) (ß = -0.30, P = 6.62 × 10-32 ) was also inversely associated with c-peptide and positively associated with adiponectin. Adjustment for BMI attenuated the metabolite-biomarker associations more for hemoglobin A1c (> 100%) and c-peptide (58.8% to > 100%) than for C-reactive protein (10.5%-40.0%) and adiponectin (7.0%-30.4%). CONCLUSIONS: These results add to the list of metabolites associated with adiposity and indicate that some may influence processes that contribute to the development of obesity-related diseases.


Assuntos
Biomarcadores/sangue , Índice de Massa Corporal , Diabetes Mellitus/fisiopatologia , Inflamação/fisiopatologia , Metabolômica/métodos , Circunferência da Cintura/fisiologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino
10.
Eur Urol Oncol ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31378665

RESUMO

BACKGROUND: Little is known about the underlying molecular mechanisms of prostate cancer, especially advanced and fatal prostate cancer. OBJECTIVE: To examine associations of prediagnostic plasma metabolomic profiles with advanced and fatal prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: In a case-cohort study of the Cancer Prevention Study-II Nutrition Cohort, of 14 210 cancer-free men with a blood sample in 1998-2001, 129 were diagnosed with advanced prostate cancer (T3-T4 or N1 or M1) through June 2013 and 112 died from prostate cancer through December 2014. Plasma samples from advanced and fatal cases, and a randomly selected subcohort of 347 men were metabolically profiled using untargeted mass spectroscopy-based platforms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prentice-weighted Cox proportional hazards regression models were used to assess associations of 699 known metabolites with advanced and fatal prostate cancer. RESULTS AND LIMITATIONS: Two metabolites derived from fatty acid metabolism (ethylmalonate and butyrylcarnitine), aspartate, sphingomyelin (d18:1/18:0), and two γ-glutamyl amino acids (γ-glutamylmethionine and γ-glutamylglutamine) were statistically significantly associated (false discovery rate <0.2) with fatal prostate cancer. One standard deviation (SD) increase in each γ-glutamyl amino acid was associated with 34-38% decreased risk, whereas one SD increase in each of the other metabolites was associated with 45-53% increased risk. A metabolic risk score based on four of these metabolites (excluding butyrylcarnitine and γ-glutamylglutamine, which were not independent predictors) was strongly associated with fatal prostate cancer (relative risk per SD: 2.72, 95% confidence interval: 2.05-3.60). No metabolites were statistically significantly associated with advanced prostate cancer. These results were observational and may not be causal. CONCLUSIONS: These findings identified metabolic pathways that are altered in the development of fatal prostate cancer. Further research into these pathways may provide insights into the etiology of fatal prostate cancer. PATIENT SUMMARY: In a large follow-up study of cancer-free men, those with a certain metabolomic profile had a higher risk of dying from prostate cancer.

11.
Am J Clin Nutr ; 109(5): 1439-1451, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31051511

RESUMO

BACKGROUND: Healthy diet patterns are associated with lower risk of cancer and other chronic diseases. Metabolomics has the potential to expand dietary biomarker development to include dietary patterns, which may provide a complement or alternative to self-reported diet. OBJECTIVE: This study examined the correlation of serum untargeted metabolomic markers with 4 diet pattern scores-the alternate Mediterranean diet score (aMED), alternate Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Healthy Eating Index (HEI)-2015-and used multivariate methods to identify discriminatory metabolites for each pattern. METHODS: Among 1367 US postmenopausal women with serum metabolomic data in the Cancer Prevention Study-II Nutrition Cohort, we conducted partial correlation analysis, adjusted for demographic and lifestyle variables, to examine cross-sectional correlations between serum metabolomic markers and healthy diet pattern scores. In a randomly selected "training" set (50%), we conducted orthogonal partial least-squares discriminant analysis to identify metabolites that discriminated the top from bottom diet score quintiles. Combinations of metabolites with a variable importance in projection (VIP) score ≥2.5 were tested for predictability in the "testing" set based on the use of receiver operating characteristic curves. RESULTS: Out of 1186 metabolites, 32 unique metabolites were considered discriminatory based on a VIP score ≥2.5 in the training dataset with some overlap across scores (aMED = 16; AHEI = 17; DASH = 13; HEI = 12). Spearman partial correlation analyses, applying a cut-point (|r| ≥ 0.15) and Bonferroni correction (P < 1.05 × 10-5), identified similar key metabolites. The top 5 metabolites for each pattern mostly distinguished high compared with low scores; 4 of the 5 (fish-derived) metabolites were the same for aMED and AHEI, 2 of which were identified for HEI; 4 DASH metabolites were unique. CONCLUSIONS: Metabolomic methods that used a split-sample approach identified potential biomarkers for 4 healthy diet patterns. Similar metabolites across scores reflect fish consumption in healthy dietary patterns. These findings should be replicated in independent populations.


Assuntos
Dieta Saudável , Dieta Mediterrânea , Abordagens Dietéticas para Conter a Hipertensão , Comportamento Alimentar , Metabolômica/métodos , Avaliação Nutricional , Pós-Menopausa/sangue , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/prevenção & controle , Estudos Prospectivos , Estados Unidos
12.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
13.
Br J Haematol ; 186(2): 243-254, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30977126

RESUMO

There is insufficient evidence linking excess body weight to risk of myeloid malignancies. We investigated this association using data from the Cancer Prevention Study-II (CPS-II), and a meta-analysis of published cohort studies. Among 152 090 CPS-II participants, 387 acute myeloid leukaemias (AML), 100 chronic myeloid leukaemias (CML) and 170 MDS were identified over 21 years of follow-up. In CPS-II, body mass index (BMI) was weakly associated with risk of CML (hazard ratio [HR] = 1·04, 95% confidence interval [CI]: 0·99-1·09 per 1 unit increase in BMI), AML (HR = 1·01, 95% CI: 0·98-1·03) and MDS (HR = 1·03, 95% CI: 0·99-1·07). After controlling for other anthropometric factors, no clear association was observed for height, BMI at age 18 years or weight change. In the meta-analysis (n = 7117 myeloid leukaemias), BMI 25-29·9 kg/m2 (HRpooled  = 1·36, 95% CI: 1·12-1·59) and BMI ≥30 kg/m2 (HRpooled  = 1·43, 95% CI: 1·18-1·69) were associated with higher risk of myeloid leukaemia overall, compared to a BMI <25 kg/m2 . Likewise, BMI ≥25 kg/m2 was positively associated with both AML and CML risk individually in the meta-analysis. These results underscore the need for large studies to detect associations with rare cancers, and show a modest, but positive association between excess body weight and myeloid malignancy risk.


Assuntos
Estatura , Índice de Massa Corporal , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Fatores Etários , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/fisiopatologia , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
14.
Br J Cancer ; 120(6): 647-657, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787463

RESUMO

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Teorema de Bayes , Neoplasias da Mama/metabolismo , Cromossomos Humanos Par 7 , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo
16.
Am J Hum Genet ; 104(1): 21-34, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554720

RESUMO

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Predisposição Genética para Doença , Herança Multifatorial/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Anamnese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/metabolismo , Reprodutibilidade dos Testes , Medição de Risco
17.
Cancer Res ; 78(20): 6011-6021, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30185547

RESUMO

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER+ or PR+/HER2-), 1,368 luminal B-like (ER+ or PR+/HER2+), 521 HER2-enriched (ER-/PR-/HER2+), and 1,152 triple-negative (ER-/PR-/HER2-) disease. Ever parous compared with never was associated with lower risk of luminal A-like (HR, 0.78; 95% CI, 0.73-0.83) and luminal B-like (HR, 0.74; 95% CI, 0.64-0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02-1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011-21. ©2018 AACR.


Assuntos
Neoplasias da Mama/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores de Progesterona/metabolismo , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
18.
Metabolites ; 8(4)2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30248901

RESUMO

Over-the-counter analgesic use is common and is typically assessed through self-report; therefore, it is subject to misclassification. Detection of drug metabolites in biofluids offers a viable tool for validating self-reported analgesic use. Thus, the aim of this study was to determine the utility of a metabolomics approach for the validation of acetaminophen and ibuprofen use in blood samples. Untargeted mass spectrometry-based metabolomics analysis was conducted in serum samples from 1547 women and plasma samples from 556 men. The presence of two metabolites each for acetaminophen and ibuprofen at levels at or above a defined cutoff value was used to determine concordance with self-reported use. For acetaminophen use based on the presence of both acetaminophen and acetamidophenylglucuronide, concordance was 98.5⁻100% among individuals reporting use today, and 79.8⁻91.4% for those reporting never or rare use. Ibuprofen use based on the presence of both carboxyibuprofen and hydroxyibuprofen resulted in concordance of 51.3⁻52.5% for individuals reporting use today and 99.4⁻100% for those reporting never or rare use. Our findings suggest that an untargeted metabolomics approach in blood samples may be useful for validating self-reported acetaminophen use. However, this approach appears unlikely to be suitable for validating ibuprofen use.

19.
Nat Genet ; 50(7): 968-978, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.


Assuntos
Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único , Risco , Transcriptoma
20.
Nat Genet ; 50(7): 928-936, 2018 07.
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.


Assuntos
Neoplasias da Próstata/genética , Estudos de Casos e Controles , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Risco
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