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2.
Sci Rep ; 9(1): 18142, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792337

RESUMO

Genetic risk score (GRS) is used to demonstrate the genetic variants contributing to the polygenic architecture of complex diseases. By using a GRS, we have investigated the additive impact of the known adult glioma susceptibility loci on the pediatric brain tumor (PBT) risk and assessed the proportion of PBT heritability attributable to these susceptibility loci. A GRS was generated for PBTs based on the alleles and associated effect sizes derived from a previously published genome-wide association study on adult glioma. The GRS was calculated in CEFALO, a population-based case-control study of brain tumors in children and adolescents including saliva DNA of 245 cases and 489 controls. The unconditional logistic regression model was used to investigate the association between standardized GRS and risk of PBTs. To measure the variance explained by the effect of GRS, Nagelkerke pseudo-R2 was calculated. The GRS for adult brain tumors was associated with an increased risk of PBTs (OR 1.25 [95% CI 1.06-1.49], p = 0.009) and 0.3% of the variance in PBTs could be explained by the effect of GRS on the liability scale. This study provides evidence that heritable risks of PBTs are in-part attributable to some common genetic variants associated with adult glioma.

4.
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
5.
Breast Cancer Res ; 19(1): 29, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28288659

RESUMO

BACKGROUND: Most mammography screening programs are not individualized. To efficiently screen for breast cancer, the individual risk of the disease should be determined. We describe a model that could be used at most mammography screening units without adding substantial cost. METHODS: The study was based on the Karma cohort, which included 70,877 participants. Mammograms were collected up to 3 years following the baseline mammogram. A prediction protocol was developed using mammographic density, computer-aided detection of microcalcifications and masses, use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, age, and body mass index. Relative risks were calculated using conditional logistic regression. Absolute risks were calculated using the iCARE protocol. RESULTS: Comparing women at highest and lowest mammographic density yielded a fivefold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly ninefold higher risk of breast cancer than those at lowest risk. In the full model, taking HRT use, family history of breast cancer, and menopausal status into consideration, the AUC reached 0.71. CONCLUSIONS: Measures of mammographic features and information on HRT use, family history of breast cancer, and menopausal status enabled early identification of women within the mammography screening program at such a high risk of breast cancer that additional examinations are warranted. In contrast, women at low risk could probably be screened less intensively.


Assuntos
Neoplasias da Mama/epidemiologia , Modelos Teóricos , Adulto , Idoso , Área Sob a Curva , Densidade da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Simulação por Computador , Detecção Precoce de Câncer , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Mamografia , Programas de Rastreamento , Pessoa de Meia-Idade , Risco , Fatores de Risco , Suécia/epidemiologia
6.
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
7.
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
8.
Breast Cancer Res ; 18(1): 98, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27716369

RESUMO

BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Quinase do Ponto de Checagem 2/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Análise por Conglomerados , Códon , Europa (Continente)/epidemiologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Heterozigoto , Humanos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transcriptoma
9.
Sci Rep ; 6: 32512, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27600471

RESUMO

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Proteínas de Transporte Vesicular/genética , Neoplasias da Mama/patologia , Mapeamento Cromossômico , Cromossomos Humanos Par 17/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
10.
Cancer Epidemiol Biomarkers Prev ; 25(11): 1503-1510, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27550749

RESUMO

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.


Assuntos
Índice de Massa Corporal , Neoplasias do Endométrio/etiologia , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Neoplasias do Endométrio/genética , Feminino , Humanos , Obesidade/genética , Relação Cintura-Quadril
11.
Am J Hum Genet ; 98(6): 1159-1169, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27259051

RESUMO

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.


Assuntos
Cromossomos Humanos Par 14/genética , Neoplasias do Endométrio/genética , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Uterinas/genética , Fator de Transcrição YY1/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Fatores de Risco , Transdução de Sinais , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Fator de Transcrição YY1/genética
12.
Nat Genet ; 48(6): 667-674, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27135401

RESUMO

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 8 , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
13.
Nat Commun ; 7: 11375, 2016 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-27117709

RESUMO

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Receptores Estrogênicos/genética , Proteína BRCA1/genética , Cromossomos Humanos Par 2/genética , Ciclofilinas/genética , Feminino , Genótipo , Heterozigoto , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco , tRNA Metiltransferases
14.
Int J Cancer ; 139(6): 1303-1317, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27087578

RESUMO

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Variação Genética , Locos de Características Quantitativas , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco
15.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco
16.
J Clin Oncol ; 34(3): 251-8, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26628467

RESUMO

PURPOSE: The association between established risk factors for breast cancer and subtypes or prognosis of the disease is not well known. We analyzed whether the Tyrer-Cuzick-predicted 10-year breast cancer risk score (TCRS), mammographic density (MD), and a 77-single nucleotide polymorphism polygenic risk score (PRS) were associated with breast cancer tumor prognosticators and risk of distant metastasis. PATIENTS AND METHODS: We used a case-only design in a population-based cohort of 5,500 Swedish patients with breast cancer. Logistic and multinomial logistic regression of outcomes, estrogen receptor (ER) status, lymph node involvement, tumor size, and grade was performed with TCRS, PRS, and percent MD as exposures. Cox proportional hazard models were used to estimate hazard ratios (HRs) of distant metastasis. RESULTS: Women at high risk for breast cancer based on PRS and/or TCRS were significantly more likely to be diagnosed with favorable prognosticators, such as ER-positive and low-grade tumors. In contrast, PRS weighted on ER-negative disease was associated with ER-negative tumors. When stratifying by age, the associations of TCRS with favorable prognosticators were restricted to women younger than age 50. Women scoring high in both TCRS and PRS had a lower risk of distant metastasis (HR, 0.69; 95% CI, 0.49 to 0.98). MD was not associated with any of the examined prognosticators. CONCLUSION: Women at high risk for breast cancer based on genetic and lifestyle factors were significantly more likely to be diagnosed with breast cancers with a favorable prognosis. Better knowledge of subtype-specific risk factors could be vital for the success of prevention programs aimed at lowering mortality.


Assuntos
Neoplasias da Mama/diagnóstico , Densidade da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Estilo de Vida , Modelos Logísticos , Glândulas Mamárias Humanas/anormalidades , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Suécia/epidemiologia
17.
Endocr Relat Cancer ; 23(2): 77-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26574572

RESUMO

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.


Assuntos
Aromatase/genética , Neoplasias do Endométrio/etiologia , Estradiol/sangue , Interação Gene-Ambiente , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Fatores Etários , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Estudos de Associação Genética , Humanos , Fenótipo
18.
Sci Rep ; 5: 17369, 2015 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-26621817

RESUMO

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.


Assuntos
Neoplasias Colorretais/genética , Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas Repressoras
19.
PLoS One ; 10(10): e0140563, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26469178

RESUMO

BACKGROUND: Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assessments are built on a long, empirically-based, and stringent approach. There is ample evidence that QoL is, in part, heritable. We therefore performed a GWAS relating genetic variation to QoL in healthy females. METHODS: In 5,142 healthy females, background characteristics (e.g. demographic, clinical, lifestyle and psychological factors) and QoL by means of the EORTC QLQ-C30 were measured. Moreover, women were genotyped using a custom array including ~210,000 single nucleotide polymorphisms (SNPs). Initially, SNPs were related to each QoL-domain, by means of partially adjusted (controlling for age and population stratification) and fully adjusted (controlling for age, population stratification, and background characteristics) regression analyses. Additionally, gene-based analyses were performed relating the combined effect of SNPs within each gene to QoL using the statistical software package VEGAS. RESULTS: None of the associations between QoL and genetic variation (i.e. individual SNPs and genes) reached the bonferroni corrected significance level. CONCLUSION: Reasons for a lack of association between genetic markers and QoL could be low variation in QoL-scores; selecting genetic markers not tagging QoL; or that the genetic effect that impacts one's QoL is mediated through biological pathways rather than the effect of single SNPs or genes. Therefore, we opt for a pathway-based or system biology approach as a complementary and powerful approach to analyze the combined effect of genes and their biological implications in future studies focusing on QoL-issues.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Qualidade de Vida , Adulto , Idoso , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Suécia
20.
Endocr Relat Cancer ; 22(5): 851-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26330482

RESUMO

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.


Assuntos
Neoplasias da Mama/genética , Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Biologia Computacional , Proteínas do Citoesqueleto , Bases de Dados Genéticas , Feminino , Loci Gênicos , Genótipo , Humanos , Metanálise como Assunto , Prognóstico , Regiões Promotoras Genéticas/genética , Fatores de Risco
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