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1.
Artigo em Inglês | MEDLINE | ID: mdl-33144283

RESUMO

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel sub-genome wide regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation. CONCLUSION: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

2.
Hum Mutat ; 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32623769

RESUMO

It is possible to estimate the prior probability of pathogenicity for germline disease gene variants based on bioinformatic prediction of variant effect/s. However, routinely used approaches have likely led to the underestimation and underreporting of variants located outside donor and acceptor splice site motifs that affect messenger RNA (mRNA) processing. This review presents information about hereditary cancer gene germline variants, outside native splice sites, with experimentally validated splicing effects. We list 95 exonic variants that impact splicing regulatory elements (SREs) in BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2. We utilized a pre-existing large-scale BRCA1 functional data set to map functional SREs, and assess the relative performance of different tools to predict effects of 283 variants on such elements. We also describe rare examples of intronic variants that impact branchpoint (BP) sites and create pseudoexons. We discuss the challenges in predicting variant effect on BP site usage and pseudoexonization, and suggest strategies to improve the bioinformatic prioritization of such variants for experimental validation. Importantly, our review and analysis highlights the value of considering impact of variants outside donor and acceptor motifs on mRNA splicing and disease causation.

3.
Cancers (Basel) ; 12(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936698

RESUMO

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

4.
Genet Med ; 22(5): 847-856, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31965077

RESUMO

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

6.
Cancers (Basel) ; 11(10)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561579

RESUMO

The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer-promoter interactions, a mechanism through which GWAS variation may target genes, we captured chromatin loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their targeting. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from normal and tumoral endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.

7.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1095-1102, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31040137

RESUMO

Endometrial cancer, the most commonly diagnosed cancer of the female reproductive tract in developed countries, has a heritable component. To date, 16 genetic risk regions have been robustly discovered by genome-wide association studies (GWAS) of endometrial cancer. Post-GWAS analyses including expression quantitative trait loci analysis and laboratory-based functional studies have been successful in identifying genes and pathways involved in endometrial carcinogenesis. Mendelian randomization analysis studies have confirmed factors causal for endometrial cancer risk, including increased body mass index and early onset of menarche. In this review, we summarize findings from GWAS and post-GWAS analyses of endometrial cancer. We discuss clinical implications of these findings, current knowledge gaps, and future directions for the study of endometrial cancer genetics.


Assuntos
Neoplasias do Endométrio/genética , Estudo de Associação Genômica Ampla/métodos , Feminino , Humanos
8.
Front Oncol ; 9: 182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972295

RESUMO

Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10-8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87-1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89-1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53-1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.

9.
Cancer Res ; 79(1): 231-241, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385613

RESUMO

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. SIGNIFICANCE: Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/mortalidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Renais/mortalidade , Mutação , Sorafenibe/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Proliferação de Células , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
10.
Genet Med ; 21(7): 1486-1496, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30504929

RESUMO

PURPOSE: To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data. METHODS: Two sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories. RESULTS: Concordance between the training runs met our prespecified validation criterion. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible. CONCLUSION: The CIMRA assay accurately predicts pathogenic and benign MMR gene variants. Quantitative combination of assay results with in silico analysis correctly classified the majority of variants. Using this calibration, CIMRA assay results can be integrated into the diagnostic algorithm for MMR gene variants.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Técnicas Genéticas , Células 3T3 , Animais , Teorema de Bayes , Calibragem , Simulação por Computador , Humanos , Técnicas In Vitro , Camundongos , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
PLoS One ; 13(8): e0202272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30107003

RESUMO

PURPOSE: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. PATIENTS AND METHODS: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. RESULTS: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. CONCLUSION: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Receptores de Calcitriol/genética , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Vitamina D/sangue
12.
Nat Commun ; 9(1): 3166, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093612

RESUMO

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Alelos , Cromatina/química , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Transdução de Sinais
14.
Front Pharmacol ; 8: 896, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29270124

RESUMO

The development of new drugs has become challenging as the necessary investments in time and money have increased while drug approval rates have decreased. A potential solution to this problem is drug repositioning which aims to use existing drugs to treat conditions for which they were not originally intended. One approach that may enhance the likelihood of success is to reposition drugs against a target that has a genetic basis. The multitude of genome-wide association studies (GWASs) conducted in recent years represents a large potential pool of novel targets for drug repositioning. Although trait-associated variants identified from GWAS still need to be causally linked to a target gene, recently developed functional genomic techniques, databases, and workflows are helping to remove this bottleneck. The pre-clinical validation of repositioning against these targets also needs to be carefully performed to ensure that findings are not confounded by off-target effects or limitations of the techniques used. Nevertheless, the approaches described in this review have the potential to provide a faster, cheaper and more certain route to clinical approval.

15.
Oncotarget ; 8(39): 64670-64684, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029385

RESUMO

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

16.
Nature ; 551(7678): 92-94, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29059683

RESUMO

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.


Assuntos
Neoplasias da Mama/genética , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Ásia/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Sítios de Ligação/genética , Neoplasias da Mama/diagnóstico , Simulação por Computador , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico , Medição de Risco , Fatores de Transcrição/metabolismo
17.
Front Pharmacol ; 8: 218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28487654

RESUMO

After menopause, estradiol is primarily synthesized in peripheral tissues by the enzyme aromatase, encoded by CYP19A1. CYP19A1 variation associates with circulating estradiol in postmenopausal women and this variation is best represented by the intronic variant rs727479. This variation appears to have pleiotropic effects as it also associates with endometrial cancer risk. Indeed, estradiol plays an important role in the development of breast and endometrial cancer. Aromatase inhibitor (AI) drugs are used in the treatment of both diseases, however, response rates for AIs are low and there is currently no way to identify breast or endometrial cancer patients who are more likely to receive a clinical benefit. Multiple studies have proposed that genetic variation in CYP19A1 will have effects on AI efficacy: eight candidate variant studies of sample size greater than 50 describe associations between CYP19A1 variation and the outcome of patients treated with AIs. Nominally significant associations with patient outcome were reported for several variants, including rs727479. However, only an association between rs4646 and time to progression was replicated in an independent study. Moreover, rs4646 is also the only variant that has an association with patient outcome that passes a multiple testing threshold and this variant is in linkage disequilibrium with rs727479, supporting the hypothesis that associations with patient outcome may be driven through the effects on circulating estradiol. Despite this preliminary evidence, well phenotyped and comprehensively genotyped patient sets need to be studied before conclusions can be drawn about the effects of CYP19A1 variation on AI efficacy.

18.
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
19.
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
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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