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1.
Am J Epidemiol ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509174

RESUMO

Despite research efforts, current knowledge on the etiology of thyroid carcinoma remains limited. To explore the potential role of diet-induced inflammation, we examined the association between differentiated thyroid cancer risk and the energy-adjusted Dietary Inflammatory Index (E-DII®) in a population-based case-control study conducted in New Caledonia - a Pacific archipelago with one of the highest recorded thyroid cancer incidence rates in the world. The E-DII was computed from food frequency questionnaire information on usual dietary intake. Logistic regression analyses were performed on data from 324 histologically confirmed cases of papillary or follicular carcinoma diagnosed from 1993 to 1999 and 402 controls. Positive associations between E-DII and thyroid cancer risk were observed (odds ratio, 1.67; 95% confidence interval: 1.08, 2.58; P-trend = 0.002; comparing extreme tertiles), with stronger associations found for larger carcinomas (P-trend = 0.0005). Stratified analyses showed an increased risk of thyroid cancer associated with the E-DII among Southern province residents (P-trend = 0.003), Melanesian women (P-trend = 0.02), obese participants (Ptrend = 0.006) and ever smokers (P-trend = 0.0005). Our results suggest that a proinflammatory diet - especially when concomitant with other inflammation-inducing conditions or habits (e.g., obesity, smoking) - is associated with increased risk of thyroid carcinoma.

2.
Int J Cancer ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31342519

RESUMO

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow-up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country-specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval [CI] 0.77-1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80-1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55-2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p-trend = 0.019) and phenolic acids (p-trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.

3.
Int J Cancer ; 145(7): 1745-1753, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665264

RESUMO

Circadian rhythms regulate several physiological functions and genes controlling the circadian rhythm were found to regulate cell proliferation, cell cycle and apoptosis. Few studies have investigated the role of those circadian genes in prostate cancer occurrence. We aim to investigate the relationship between circadian genes polymorphisms and prostate cancer risk based on data from the EPICAP study, a population-based case-control study including 1,515 men (732 cases / 783 controls) with genotyped data. Odds Ratios (ORs) for association between prostate cancer and circadian gene variants were estimated for each of the 872 single nucleotide polymorphisms (SNPs) in 31 circadian clock genes. We also used a gene-based and pathway-based approach with a focus on the pathway including 9 core circadian genes. Separate analyses were conducted by prostate cancer aggressiveness. The core-circadian pathway (p = 0.0006) was significantly associated to prostate cancer, for either low (p = 0.002) or high (p = 0.01) grade tumor. At the gene level, we observed significant associations between all prostate cancer and NPAS2 and PER1 after correcting for multiple testing, while only RORA was significant for aggressive tumors. At the SNP-level, no significant association was observed. Our findings provide additional evidence of a potential link between genetic variants in circadian genes and prostate cancer risk. Further investigation is warranted to confirm these findings and to better understand the biological pathways involved.

4.
Int J Cancer ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30303517

RESUMO

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1125 cases and 1172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with pre-menopausal breast cancer risk (p=0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p=0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke. This article is protected by copyright. All rights reserved.

5.
Int J Epidemiol ; 47(2): 526-536, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315403

RESUMO

Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests). Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.

6.
Int J Cancer ; 141(9): 1830-1840, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28670784

RESUMO

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.


Assuntos
Neoplasias da Mama/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Interação Gene-Ambiente , Estudos de Associação Genética , Consumo de Bebidas Alcoólicas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/genética
7.
Cancer Epidemiol ; 48: 78-84, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28426980

RESUMO

The three times higher incidence of thyroid cancer in women compared to men points to a role of female sex hormones in its etiology. However the effects of these factors are poorly understood. We analyzed the association between thyroid cancer and hormonal and reproductive factors among women enrolled in CATHY, a population-based case-control study conducted in France. The study included 430 cases of papillary thyroid cancer and 505 controls frequency-matched on age and area of residence. The odds ratios for thyroid cancer increased with age at menarche (p trend 0.05). Postmenopausal women were at increased risk, as compared to premenopausal women, particularly if menopause followed an ovariectomy, and for women with age at menopause <55years. In addition, use of oral contraceptives and menopausal hormone therapy reduced the association with thyroid cancer by about one third, and breastfeeding by 27%. Overall, these findings provide evidence that the risk of thyroid cancer increases with later age at menarche and after menopause, and decreases with use of oral contraceptives and menopausal hormone therapy. These findings confirm an implication of hormonal factors in papillary thyroid cancer risk, whose mechanisms need to be elucidated.


Assuntos
Carcinoma Papilar/complicações , Terapia de Reposição Hormonal/métodos , Neoplasias da Glândula Tireoide/complicações , Adulto , Idoso , Estudos de Casos e Controles , Feminino , França , Humanos , Pessoa de Meia-Idade , História Reprodutiva , Projetos de Pesquisa , Fatores de Risco , Câncer Papilífero da Tireoide
8.
Am J Hum Genet ; 99(4): 903-911, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27640304

RESUMO

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Cromossomos Humanos Par 5/genética , Fator 10 de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/metabolismo , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Fator 10 de Crescimento de Fibroblastos/metabolismo , Haplótipos/genética , Humanos , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
9.
BMC Cancer ; 16(1): 761, 2016 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-27681230

RESUMO

BACKGROUND: Overweight and weight gain throughout adult life have been associated with increased risk of breast cancer after the menopause. However the role of body weight at a young age and of the timing of weight gain over the lifetime in postmenopausal breast cancer is not well documented. METHODS: We conducted a population-based case-control study on breast cancer in France that included 739 cases and 815 population controls in postmenopausal women. Height, weight at age 20, 40 and 50 as well as weight one year before diagnosis were obtained during in-person interviews. RESULTS: No association between body mass index at the age of 20 years and breast cancer after the menopause was detected. However, we found that postmenopausal breast cancer was associated with weight gain between ages 40 and 50 years (OR per 5 kg/m2 increase in BMI: 1.45 [95%ci 1.06-1.98]). The increased risk of breast cancer associated with weight gain was more consistent in leaner women at age 20, in older postmenopausal women (>65 years), and in women who did not use menopausal hormone therapy. CONCLUSIONS: These findings point to the importance of controlling for weight gain in middle aged-women. The role of low body weight in young adulthood in breast cancer risk after the menopause should be further scrutinized.

10.
J Med Genet ; 53(12): 800-811, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27595995

RESUMO

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/metabolismo , Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Risco
11.
PLoS One ; 11(8): e0160316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27556229

RESUMO

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.


Assuntos
Neoplasias da Mama/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Locos de Características Quantitativas , Alelos , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Gradação de Tumores , Polimorfismo de Nucleotídeo Único , Vigilância da População , Medição de Risco
12.
Hum Mol Genet ; 25(17): 3863-3876, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27402876

RESUMO

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 2/genética , Elementos Facilitadores Genéticos , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Deleção de Sequência , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto Jovem
13.
PLoS One ; 11(5): e0153788, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27149063

RESUMO

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Mama/etiologia , Proteínas de Ligação a DNA/fisiologia , Feminino , Finlândia , Predisposição Genética para Doença/genética , Técnicas de Genotipagem , Haplótipos/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto
14.
Chronobiol Int ; 33(6): 783-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27078711

RESUMO

Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.


Assuntos
Neoplasias da Mama/metabolismo , Ritmo Circadiano/fisiologia , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Risco
15.
Nat Genet ; 48(4): 374-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26928228

RESUMO

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 6/genética , Receptor alfa de Estrogênio/genética , Sequência de Bases , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Risco
16.
Int J Cancer ; 139(3): 617-27, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-26991144

RESUMO

Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , França , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Melanesia , Pessoa de Meia-Idade , Nova Caledônia , Razão de Chances , Vigilância da População , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia
17.
Hosp Pediatr ; 6(2): 88-94, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26753631

RESUMO

BACKGROUND AND OBJECTIVES: Within hospital pediatric units, there is a lack of consistent application or modeling of the American Academy of Pediatrics recommendations for safe infant sleep. The purpose of this study was to improve safe sleep practices for infants in nonneonatal pediatric units with implementation of specific interventions. METHODS: This multi-institutional study was conducted by using baseline observations collected for sleep location, position, and environment (collectively, "safe sleep") of infants admitted to pediatric units. Interventions consisted of: (1) staff education, including a commitment to promote safe sleep; (2) implementing site-generated safe sleep policies; (3) designating supply storage in patient rooms; and/or (4) caregiver education. Postintervention observations of safe sleep were collected. Eight hospitals participated from the Inpatient FOCUS Group of the Children's Hospital Association. Each site received institutional review board approval/exemption. RESULTS: Safe sleep was observed for 4.9% of 264 infants at baseline and 31.2% of 234 infants postintervention (P<.001). Extra blankets, the most common of unsafe items, were present in 77% of cribs at baseline and 44% postintervention. However, the mean number of unsafe items observed in each sleeping environment was reduced by >50% (P=.001). CONCLUSIONS: Implementation of site-specific interventions seems to improve overall safe sleep in inpatient pediatric units, although continued improvement is needed. Specifically, extra items are persistently left in the sleeping environment. Moving forward, hospitals should evaluate their compliance with American Academy of Pediatrics recommendations and embrace initiatives to improve modeling of safe sleep.


Assuntos
Ambiente de Instituições de Saúde/normas , Cuidado do Lactente , Segurança do Paciente/normas , Sono , Criança Hospitalizada/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Hospitais Pediátricos/normas , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Cuidado do Lactente/métodos , Cuidado do Lactente/normas , Masculino , Pediatria/métodos , Pediatria/normas , Melhoria de Qualidade , Estados Unidos
18.
Hum Genet ; 135(1): 137-54, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26621531

RESUMO

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Tolerância Imunológica/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Humanos
19.
J Natl Cancer Inst ; 108(2)2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26586665

RESUMO

BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Códon de Terminação , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Modelos Logísticos , Lisina/genética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Razão de Chances , Neoplasias Ovarianas/patologia , Medição de Risco , Fatores de Risco
20.
J Natl Cancer Inst ; 107(11)2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26296642

RESUMO

BACKGROUND: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. METHODS: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. RESULTS: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8). CONCLUSIONS: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.


Assuntos
Estatura , Neoplasias da Mama/epidemiologia , Medicina Baseada em Evidências , Feminino , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Estudos Prospectivos , Fatores de Risco
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