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1.
Cancer Epidemiol Biomarkers Prev ; 28(4): 822-825, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30642840

RESUMO

BACKGROUND: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. METHODS: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. RESULTS: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. CONCLUSIONS: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. IMPACT: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.

2.
Breast J ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30414230

RESUMO

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations. METHODS: We included all breast cancers from female patients tested at our institute between 1992 and 2016 (n = 3469) for which pathology data were available. ILC proportion comparison according to mutational status was performed by a chi-squared test. The impact of susceptibility genes on ILC proportion was investigated by univariate logistic regression with wild-type patients as reference. RESULTS AND DISCUSSION: There were 265 (7.64%) ILC: 2/342 (0.58%) in BRCA1 patients, 24/238 (10%) in BRCA2 patients, 1/57 (1.75%) in TP53 patients and 238/2832 (8.4%) in non-carriers. The majority of breast cancers in all groups were invasive ductal and ductal in situ carcinomas. The difference in ILC proportion was highly significant (P < 0.001). Compared to wild-type patients, BRCA1 was associated with a lower ILC proportion (OR 0.064 [95% CI 0.016;0.259], P < 0.0001). BRCA2 OR was 1.222 [95%CI 0.785;1.902] (P = 0.374), TP53 OR was 0.195 [95%CI 0.027;1.412] (P = 0.105). ILC are therefore underrepresented in BRCA1 and TP53 mutation carriers. Formal significance (P = 0.05) was not reached for TP53, but statistical power was only 38%. Based on ILC incidence in the general population, we make the hypothesis that BRCA1 and TP53 do not predispose to ILC, as the few occurrences of ILC in mutation carriers could be attributed to chance and not to germline mutations. Our observations will be useful to clinical cancer geneticists managing patients with ILC, as a BRCA1 or TP53 mutation in these patients would be unlikely. Genetic counseling should be adapted accordingly.

3.
Nat Genet ; 50(7): 968-978, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

4.
J Med Genet ; 55(2): 97-103, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28993434

RESUMO

BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.

5.
Nat Genet ; 49(12): 1767-1778, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058716

RESUMO

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Heterozigoto , Humanos , Receptores Estrogênicos/metabolismo , Fatores de Risco
6.
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
7.
J Med Genet ; 54(11): 732-741, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28779002

RESUMO

BACKGROUND: Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. METHODS: Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. RESULTS: Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. CONCLUSIONS: Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas Mutadas de Ataxia Telangiectasia/química , Quinase do Ponto de Checagem 2/química , Proteínas de Ligação a DNA/química , Proteína do Grupo de Complementação N da Anemia de Fanconi/química , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Análise de Sequência de Proteína
8.
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
9.
Breast Cancer Res ; 18(1): 64, 2016 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-27459855

RESUMO

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Proteína BRCA1/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Bases de Dados Genéticas , Elementos Facilitadores Genéticos , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Haplótipos , Heterozigoto , Humanos , Mutação , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Risco
10.
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
11.
J Natl Cancer Inst ; 108(3)2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26823519

RESUMO

Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.


Assuntos
Frequência do Gene , Mosaicismo , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fosfoproteínas Fosfatases/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteína Fosfatase 2C
12.
J Med Genet ; 52(7): 465-75, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26025000

RESUMO

BACKGROUND: Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. METHODS: We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. RESULTS: The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. CONCLUSIONS: The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process.


Assuntos
Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial/genética , Neoplasias Ovarianas/diagnóstico , Medição de Risco/métodos , Alelos , Feminino , Aconselhamento Genético/métodos , Humanos
13.
Radiother Oncol ; 111(2): 178-85, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24785509

RESUMO

BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Variação Genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Radioterapia de Intensidade Modulada/efeitos adversos , Relação Dose-Resposta à Radiação , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Radioterapia Adjuvante/efeitos adversos
14.
Hum Mol Genet ; 22(24): 502017 Apr, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23900074

RESUMO

Mean telomere length (TL) in blood cells is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2240) and selected 1629 variants for replication via the "iCOGS" custom genotyping array. All ∼200 000 iCOGS variants were analysed with TL, and those displaying associations in healthy controls (n = 15 065) were further tested in breast cancer cases (n = 11 024). We found a novel TL association (Ptrend < 4 × 10(-10)) at 3p14.4 close to PXK and evidence (Ptrend < 7 × 10(-7)) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (Ptrend < 5 × 10(-14)) the previously reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (Ptrend < 5 × 10(-4)) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Neoplasias/genética , Homeostase do Telômero/genética , Telômero/genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único , Risco , Telômero/metabolismo
15.
Am J Hum Genet ; 92(4): 489-503, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23540573

RESUMO

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 11/genética , Ciclina D1/genética , Elementos Facilitadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Sítios de Ligação , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cromatina/química , Cromatina/genética , Imunoprecipitação da Cromatina , Ciclina D1/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Fator de Transcrição GATA3/antagonistas & inibidores , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Luciferases/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Elementos Silenciadores Transcricionais/genética , Proteínas Elk-4 do Domínio ets/antagonistas & inibidores , Proteínas Elk-4 do Domínio ets/genética , Proteínas Elk-4 do Domínio ets/metabolismo
16.
Nat Genet ; 45(4): 371-84, 384e1-2, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23535731

RESUMO

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/etiologia , Loci Gênicos/genética , Neoplasias Ovarianas/etiologia , Polimorfismo de Nucleotídeo Único/genética , Telomerase/genética , Telômero/genética , Processamento Alternativo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Cromatina/genética , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Luciferases/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco
17.
Nat Genet ; 44(3): 312-8, 2012 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-22267197

RESUMO

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 21/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal
18.
Lancet Oncol ; 13(1): 65-77, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22169268

RESUMO

BACKGROUND: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. METHODS: 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. FINDINGS: None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. INTERPRETATION: We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. FUNDING: Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Fracionamento da Dose de Radiação , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Radioterapia de Intensidade Modulada/efeitos adversos , Relação Dose-Resposta à Radiação , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Lineares , Masculino , Razão de Chances , Estudos Prospectivos , Lesões por Radiação/patologia , Radioterapia Adjuvante/efeitos adversos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido
19.
PLoS One ; 6(9): e24987, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21949822

RESUMO

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.


Assuntos
Neoplasias da Mama/genética , Cistadenocarcinoma Seroso/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único/genética , Telomerase/genética , Estudos de Casos e Controles , Feminino , Humanos , Prognóstico
20.
Cancer Epidemiol Biomarkers Prev ; 20(6): 1255-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21527579

RESUMO

BACKGROUND: The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility. METHODS: DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) ≥ 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF > 0.05) in CYP2D6. RESULTS: One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (P(trend) = 0.02; OR = 1.32; 95% CI = 1.04-1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility. CONCLUSIONS: Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation. IMPACT: This large case-control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study.


Assuntos
Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Mama/metabolismo , Mama/patologia , Estudos de Casos e Controles , DNA de Neoplasias/genética , Feminino , Genótipo , Humanos , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco
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