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1.
Br J Cancer ; 124(4): 842-854, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33495599

RESUMO

BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33500318

RESUMO

BACKGROUND: It is not known if modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer-specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (adjusted p>0.30). The strongest associations were between all-cause mortality and BMI {greater than or equal to}30 vs 18.5-25 kg/m2 (HR (95%CI): 1.19 (1.06,1.34)); current vs never smoking (1.37 (1.27,1.47)), high vs low physical activity (0.43 (0.21,0.86)), age {greater than or equal to}30 years vs <20 years at first pregnancy (0.79 (0.72,0.86)); >0 to <5 years vs {greater than or equal to}10 years since last full term birth (1.31 (1.11,1.55)); ever vs never use of oral contraceptives (0.91 (0.87,0.96)); ever vs never use of menopausal hormone therapy, including current estrogen-progestin therapy (0.61 (0.54,0.69)). Similar associations with breast cancer mortality were weaker; e.g. 1.11 (1.02,1.21) for current vs never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

3.
Gut ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139268

RESUMO

OBJECTIVE: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.

4.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

5.
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.

6.
Eur J Gastroenterol Hepatol ; 32(8): 938-949, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32282540

RESUMO

OBJECTIVE: Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD. METHODS: Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls. RESULTS: Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06. CONCLUSION: IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.

7.
Nat Commun ; 11(1): 312, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949161

RESUMO

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.


Assuntos
Neoplasias da Mama/genética , Variação Genética , Estudo de Associação Genômica Ampla , Células Germinativas , Apoptose , Relógios Circadianos , Biologia Computacional , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Redes Reguladoras de Genes , Genótipo , Humanos , Prognóstico , Receptores Estrogênicos/genética , Transdução de Sinais
8.
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
9.
J Gastrointestin Liver Dis ; 28(1): 15-22, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851167

RESUMO

BACKGROUND AND AIMS: There is no literature on the role of repeat small bowel capsule endoscopy (SBCE) in patients with refractory coeliac disease (RCD) following treatment with steroids +/- immunosuppressants. METHODS: The findings on SBCEs from a group of patients with histologically proven RCD (n=23) were compared to the findings from patients with uncomplicated coeliac disease (n=48). All patients had concurrent duodenal histology and serology taken at the time of SBCE. RESULTS: Patients with RCD had a greater extent of mucosal involvement on SBCE than patients with uncomplicated CD (42.4+/-34.1% vs 9.7+/-21.7%, p=0.0001). Following treatment with steroids and / or immunosuppressants, patients with RCD had an improvement in the extent of affected small bowel mucosa (42.4+/-34.1% vs 26.4+/-28.9% p=0.012). There was no statistical difference in histology and serology taken at the time of the first and second SBCE in patients with RCD. CONCLUSIONS: Our study suggests that SBCE is valuable in documenting the extent of mucosal involvement in patients with RCD. This is the first study that delineates the value of a second look SBCE to assess improvement in the extent of disease in the small bowel following treatment.


Assuntos
Endoscopia por Cápsula , Doença Celíaca/tratamento farmacológico , Doença Celíaca/patologia , Duodeno/efeitos dos fármacos , Duodeno/patologia , Imunossupressores/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Esteroides/uso terapêutico , Adulto , Idoso , Doença Celíaca/complicações , Resistência a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
10.
Hum Mutat ; 39(5): 729-741, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29460995

RESUMO

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.


Assuntos
Proteína BRCA2/genética , Variação Genética , Modelos Genéticos , Processamento de RNA/genética , Proteína BRCA2/metabolismo , Sequência de Bases , Calibragem , Linhagem Celular , Éxons/genética , Feminino , Predisposição Genética para Doença , Humanos , Mitomicina/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
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.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Interação Gene-Ambiente , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
12.
J Clin Pathol ; 71(4): 316-322, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28844038

RESUMO

BACKGROUND: Faecal calprotectin (FC) measurement distinguishes patients with inflammatory bowel disease (IBD) from those with irritable bowel syndrome but evidence of its performance in primary care is limited. AIMS: To assess the yield of IBD from FC testing in primary care. METHODS: Retrospective review of hospital records to assess the outcome following FC testing in primary care. Investigations for all patients undergoing FC testing in a single laboratory for 6 months from 1 October 2013 to 28 February 2014 were reviewed. RESULTS: 410 patients (162 male; median age 42; range 16-91) were included. FC>50 µg/g was considered positive (FC+). 148/410 (36.1%; median age 44 (17-91)) were FC+ (median FC 116.5 µg/g (51-1770)). 122/148 FC-positive patients (82.4%) underwent further investigation. 97 (65.5%) underwent lower gastrointestinal endoscopy (LGIE), of which 7 (7.2%) had IBD. 49/262 (18.7%) FC-negative (FC-) patients (FC ≤50 µg/g) (median age 47 (19-76)) also underwent LGIE, of whom 3 (6.1%) had IBD.IBD was diagnosed in 11/410 (2.7%; 4 ulcerative colitis, 3 Crohn's disease, 4 microscopic colitis). 8/11 were FC+ (range 67-1170) and 3 FC-. At a 50 µg/g threshold, sensitivity for detecting IBD was 72.7%, specificity 64.9%, positive predictive value (PPV) 5.41% and negative predictive value 98.9%. Increasing the threshold to 100 µg/g reduced the sensitivity of the test for detecting IBD to 54.6%. CONCLUSIONS: FC testing in primary care has low sensitivity and specificity with poor PPV for diagnosing IBD. Its use needs to be directed to those with a higher pretest probability of disease. Local services and laboratories should advise general practitioners accordingly.


Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Atenção Primária à Saúde/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
13.
Int J Epidemiol ; 46(6): 1814-1822, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29232439

RESUMO

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Receptores Estrogênicos/genética , Causalidade , Europa (Continente)/epidemiologia , Feminino , Variação Genética , Humanos , Análise da Randomização Mendeliana , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Análise de Sobrevida
14.
Oncotarget ; 8(61): 102769-102782, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262523

RESUMO

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.

15.
Breast Cancer Res ; 19(1): 119, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116004

RESUMO

BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP. CONCLUSIONS: Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , História Reprodutiva , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/etiologia , Adulto Jovem
16.
Cancer Res ; 77(11): 2789-2799, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28283652

RESUMO

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Idoso , Substituição de Aminoácidos , Animais , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Camundongos , Mutação de Sentido Incorreto , Risco
17.
Genet Med ; 19(5): 599-603, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27711073

RESUMO

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Sequência , Feminino , Genes Modificadores , Predisposição Genética para Doença , Humanos , Razão de Chances , Penetrância
18.
Gut ; 66(9): 1563-1572, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27605538

RESUMO

BACKGROUND: Seronegative villous atrophy (SNVA) is commonly attributed to coeliac disease (CD). However, there are other causes of SNVA. More recently angiotensin-2-receptor-blockers (A2RBs) have been reported as an association but data on SNVA have been limited to centres evaluating complex case referrals and not SNVA in general. OBJECTIVES: To provide clinical outcomes and associations in a large prospective study overseeing all newcomers with SNVA. DESIGN: Over a 15-year period (2000-2015) we evaluated 200 adult patients with SNVA at a UK centre. A diagnosis of either seronegative CD (SNCD) or seronegative non-CD (SN-non-CD) was reached. Baseline comparisons were made between the groups, with 343 seropositive CD subjects serving as controls. RESULTS: Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-CD 69% (n=138). The human leucocyte antigen (HLA)-DQ2 and/or DQ8 genotype was present in 61%, with a 51% positive predictive value for SNCD. The breakdown of identifiable causes in the SN-non-CD group comprised infections (27%, n=54), inflammatory/immune-mediated disorders (17.5%, n=35) and drugs (6.5%, n=13; two cases related to A2RBs). However, no cause was found in 18% (n=36) and of these 72% (n=26/36) spontaneously normalised duodenal histology while consuming a gluten-enriched diet. Following multivariable logistic regression analysis an independent factor associated with SN-non-CD was non-white ethnicity (OR 10.8, 95% CI 2.2 to 52.8); in fact, 66% of non-whites had GI infections. On immunohistochemistry all groups stained positive for CD8-T-cytotoxic intraepithelial lymphocytes. However, additional CD4-T helper intraepithelial lymphocytes were occasionally seen in SN-non-CD mimicking the changes associated with refractory CD. CONCLUSIONS: Most patients with SNVA do not have CD, in particular those who are not white. Furthermore, a subgroup with no obvious aetiology will show spontaneous histological resolution while consuming gluten. These findings suggest caution in empirically prescribing a gluten-free diet without investigation.


Assuntos
Doença Celíaca , Dieta Livre de Glúten/métodos , Antígenos HLA-DQ/imunologia , Mucosa Intestinal , Transglutaminases/imunologia , Adulto , Idoso , Atrofia , Autoanticorpos/sangue , Biópsia/métodos , Doença Celíaca/dietoterapia , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Doença Celíaca/patologia , Feminino , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Microvilosidades/imunologia , Microvilosidades/patologia , Pessoa de Meia-Idade , Estudos Prospectivos , Testes Sorológicos/métodos , Estatística como Assunto , Reino Unido/epidemiologia
19.
Sci Rep ; 6: 36874, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845421

RESUMO

NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Regiões 3' não Traduzidas , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Sítios de Ligação , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
Oncotarget ; 7(49): 80140-80163, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27792995

RESUMO

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 4 , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/patologia , Canadá , Proteínas de Transporte/genética , Estudos de Casos e Controles , DNA Helicases/genética , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Proteínas Mitocondriais/genética , Razão de Chances , Fenótipo , Locos de Características Quantitativas , Medição de Risco , Fatores de Risco
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