Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 80
Filtrar
1.
Nat Commun ; 12(1): 1078, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597508

RESUMO

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

2.
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.

3.
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.

4.
Can J Cardiol ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32927020

RESUMO

BACKGROUND: Relatively few population-based studies have explored the relationship and potential mechanisms between exposure to shift work and hypertension. The study objectives for this study were to determine: (1) if history of shift work was associated with increased rates of hypertension among working adults; and, (2) if sleep quality mediated this relationship. METHODS: We conducted a population-based cohort study using data from Ontario respondents (aged 35-69) of the 2000-01 of Canadian Community Health Survey (CCHS), which was linked to administrative health data housed at Institute for Clinical Evaluative Sciences (ICES). Our sample included survey participants who were employed with no previous diagnosis of hypertension (n=7420). During a 12-year follow-up window, we determined the time of hypertension diagnosis based on a previously validated algorithm; and explored the mediating effect of sleep quality using marginal structural effect models. RESULTS: The study sample included 2079 shift workers and 5341 day workers. Shift workers reported less refreshing sleep, more trouble sleeping, and poorer sleep quality overall compared to day workers. In 12 years of follow-up, 31.3 % of workers developed hypertension. History of shift work was associated with higher hypertension rates in both men (HR=1.21, 95% CI: 1.02-1.44) and women (HR=1.26, 95% CI: 1.03-1.55). There was no evidence that these associations were mediated by past sleep quality. CONCLUSIONS: History of shift work schedules is associated with increased rates of hypertension. Shift work disrupts sleep, but further longitudinal studies are needed to determine if sleep quality mediates the association between shift work and hypertension.

5.
Nat Commun ; 11(1): 3833, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737321

RESUMO

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Ásia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Risco
6.
Sci Rep ; 10(1): 9688, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546843

RESUMO

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

7.
Nat Genet ; 52(6): 572-581, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424353

RESUMO

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Mutação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
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.

9.
Genet Epidemiol ; 44(5): 442-468, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32115800

RESUMO

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


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Feminino , Predisposição Genética para Doença , Genômica , Humanos , Medição de Risco , Transcriptoma , Proteínas de Transporte Vesicular/genética
10.
Nat Commun ; 11(1): 1217, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139696

RESUMO

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Predisposição Genética para Doença , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Receptores Estrogênicos/metabolismo , Fatores de Risco
11.
Eur J Epidemiol ; 35(6): 579-589, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32026169

RESUMO

Experimental and epidemiologic studies suggest that light at night (LAN) exposure disrupts circadian rhythm, and this disruption may increase breast cancer risk. We investigated the potential association between residential outdoor LAN and breast cancer risk. A population-based case-control study was conducted in Vancouver, British Columbia and Kingston, Ontario, Canada with incident breast cancer cases, and controls frequency matched by age in the same region. This analysis was restricted to 844 cases and 905 controls who provided lifetime residential histories. Using time-weighted average duration at each home 5-20 years prior to study entry, two measures of cumulative average outdoor LAN were calculated using two satellite data sources. Logistic regression was used to estimate the relationship between outdoor LAN and breast cancer risk, considering interactions for menopausal status and night shift work. We found no association between residential outdoor LAN and breast cancer for either measure of LAN [OR comparing highest vs. lowest tertile (DNB) = 0.95, 95% CI 0.70-1.27]. We also found no association when considering interactions for menopausal status and past/current night work status. These findings were robust to changes to years of residential data considered, residential mobility, and longer exposure windows. Our findings are consistent with studies reporting that outdoor LAN has a small effect or no effect on breast cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Ritmo Circadiano/fisiologia , Luz , Tolerância ao Trabalho Programado/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/etiologia , Colúmbia Britânica/epidemiologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Ontário/epidemiologia , Vigilância da População , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Características de Residência , Saúde da Mulher
12.
Nat Genet ; 52(1): 56-73, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911677

RESUMO

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Mapeamento Cromossômico/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Teorema de Bayes , Feminino , Humanos , Desequilíbrio de Ligação , Sequências Reguladoras de Ácido Nucleico , Fatores de Risco
13.
NPJ Breast Cancer ; 5: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31700994

RESUMO

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

14.
EBioMedicine ; 48: 203-211, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31629678

RESUMO

BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. INTERPRETATION: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.


Assuntos
Grupo com Ancestrais do Continente Asiático , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Variação Genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Caspase 8 , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Risco
15.
BMJ Innov ; 5(1): 28-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31645991

RESUMO

Background: Cervical cancer, although almost entirely preventable through cervical cancer screening (CCS) and human papillomavirus vaccination, is the leading cause of cancer deaths among women in Tanzania. Barriers to attending CCS include lack of awareness of CCS, affordability concerns regarding screening and travel cost. We aimed to compare the effectiveness of SMS (short message service) behaviour change communication (BCC) messages and of SMS BCC messages delivered with a transportation electronic voucher (eVoucher) on increasing uptake of CCS versus the control group. Methods: Door-to-door recruitment was conducted between 1 February and 13 March 2016 in randomly selected enumeration areas in the catchment areas of two hospitals, one urban and one rural, in Northern Tanzania. Women aged 25-49 able to access a mobile phone were randomised using a computer-generated 1:1:1 sequence stratified by urban/rural to receive either (1) 15 SMS, (2) an eVoucher for return transportation to CCS plus the same SMS, or (3) one SMS informing about the nearest CCS clinic. Fieldworkers and participants were masked to allocation. All areas received standard sensitisation including posters, community announcements and sensitisation similar to community health worker (CHW) sensitisation. The primary outcome was attendance at CCS within 60 days of randomisation. Findings: Participants (n=866) were randomly allocated to the BCC SMS group (n=272), SMS + eVoucher group (n=313), or control group (n=281), with 851 included in the analysis (BCC SMS n=272, SMS + eVoucher n=298, control group n=281). By day 60 of follow-up, 101 women (11.9%) attended CCS. Intervention group participants were more likely to attend than control group participants (SMS + eVoucher OR: 4.7, 95% CI 2.9 to 7.4; SMS OR: 3.0, 95% CI 1.5 to 6.2). Trial registration number: NCT02680613.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31496793

RESUMO

Purpose: Mammographic density is an important breast cancer risk factor, although it is not clear whether the association differs across breast cancer tumor subtypes. We examined the association between indicators of mammographic density and breast cancer risk by tumor subtype among postmenopausal women by investigating heterogeneity across tumor characteristics. Methods: Mammographic density measures were determined for 477 breast cancer cases and 588 controls, all postmenopausal, in Vancouver, British Columbia, using digitized screening mammograms and Cumulus software. Mammographic dense (DA), non-dense (NDA), and percent dense (PDA) areas were treated as continuous covariates and categorized into quartiles according to the distribution in controls. For cases only, tests for heterogeneity between tumor subtypes were assessed by multinomial logistic regression. Associations between mammographic density and breast cancer risk were modeled for each subtype separately through unconditional logistic regression. Results: Heterogeneity was apparent for the association of PDA with tumor size (p-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (p-heterogeneity values >0.05). Conclusion: These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.

18.
Sci Rep ; 9(1): 12524, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Deleção de Sequência , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos
20.
Mol Genet Genomic Med ; 7(6): e707, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066241

RESUMO

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/epidemiologia , Feminino , Interação Gene-Ambiente , Humanos , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA