Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
1.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
2.
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
3.
Hum Fertil (Camb) ; 23(4): 268-274, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30634870

RESUMO

The increasingly stringent laboratory-approach to diagnosing azoospermia for post-vasectomy semen analysis (PVSA) continues to be at odds with the simpler approach desired by clinicians. This study describes the analysis of 10 years of PVSA and discusses the outcome in relation to risk, cost and assesses whether more stringent procedures are required. PVSA was performed on 4788 patients initially using a 2-test strategy (16 and 20 weeks post-surgery), moving to 1 test during 2013-2014. Azoospermia was confirmed by the analysis of 10 µl of semen followed by 10 µl of centrifuged pellet. In total, there were 9260 tests with a median of 1.93 tests/patient and 18.7 weeks to clearance. Surgical failure occurred in 1.75%, falling to 1.1% between 2011 and 2016. There were no cases of unwanted pregnancy, recanalization or complaints although misdiagnosis was detected in 1 case as a result of failure to confirm patient identification. Azoospermia performed according to World Health Organization (WHO) guidelines is sufficiently robust to confirm success/failure of vasectomy. With uncertainty surrounding the diagnosis, efforts to improve detection of occasional non-motile sperm are futile, cost more and fail to reduce risk of inappropriate clearance. Misdiagnosis is more likely from patient identification error and mitigation may include reverting to the safety net of a 2-test strategy.

4.
J Clin Oncol ; 38(7): 674-685, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841383

RESUMO

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

5.
Hum Mol Genet ; 28(R2): R180-R186, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435665

RESUMO

In this short review, we examine the overlap between genes known to be mutated in the germlines of individuals at risk of breast, ovarian and prostate cancers, and their positions in DNA damage repair pathways. Cancer risk mutations have been consistently reported in certain genes at the top of these pathways, but none have been reported in others. We consider whether some of these gene products are too crucial to life for mutations to be tolerated, whilst others, further down the pathways, are less essential.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Reparo do DNA/genética , Neoplasias da Próstata/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades/genética , Feminino , Recombinação Homóloga/genética , Humanos , Masculino , Telômero/genética , Telômero/metabolismo
6.
Cancer Epidemiol Biomarkers Prev ; 28(4): 822-825, 2019 04.
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.


Assuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos
7.
Int J Cancer ; 144(5): 1195-1204, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30175445

RESUMO

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação/genética , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Prevalência
8.
Cancer Res ; 78(21): 6329-6338, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385609

RESUMO

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer/métodos , Variação Genética , Adulto , Idoso , Proteína BRCA1/genética , Densidade da Mama , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Sobrevivência Celular , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Metástase Linfática , Mamografia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Risco , Resultado do Tratamento
9.
J Med Genet ; 55(2): 97-103, 2018 02.
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.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação , Adulto , Neoplasias da Mama/etnologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Mutação em Linhagem Germinativa , Humanos , Malásia , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto
10.
J Med Genet ; 54(11): 732-741, 2017 11.
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
11.
Nat Genet ; 49(7): 1126-1132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604730

RESUMO

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fumar/epidemiologia , Homeostase do Telômero/genética
12.
JAMA Oncol ; 3(5): 636-651, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28241208

RESUMO

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.


Assuntos
Predisposição Genética para Doença/genética , Análise da Randomização Mendeliana/métodos , Neoplasias/genética , Homeostase do Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Telômero/genética
13.
Reprod Biomed Online ; 33(1): 111-3, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27085963

RESUMO

An increase in the reliance on imported donor samples has been the consequence of a continued shortage of UK donors. Disputes can arise between suppliers and purchasers if the sperm quality is not as expected, yet there appears to be no requirement for the standardization of methods for sperm processing or analysis. Following analysis of 102 donor intrauterine insemination cycles, this study demonstrates that the motile sperm concentration is significantly (P < 0.05) reduced after the necessary removal of cryoprotectant before insemination. Suppliers of donor spermatozoa should therefore provide information on standards used for sperm assessment and whether analysis is performed before or after washing in order that purchasers are better informed about the quality of the end product they are committed to buying.


Assuntos
Criopreservação/normas , Crioprotetores/química , Preservação do Sêmen/normas , Motilidade Espermática , Espermatozoides/fisiologia , Criopreservação/métodos , Humanos , Inseminação Artificial Heteróloga/métodos , Masculino , Sêmen/metabolismo , Preservação do Sêmen/métodos , Espermatozoides/patologia , Doadores de Tecidos
14.
Nat Genet ; 48(4): 374-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26928228

RESUMO

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 6/genética , Receptor alfa de Estrogênio/genética , Sequência de Bases , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Risco
15.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

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


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco
16.
Fam Cancer ; 15(1): 139-44, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26433962

RESUMO

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.


Assuntos
Predisposição Genética para Doença/genética , Melanoma/genética , Regiões Promotoras Genéticas , Telomerase/genética , Adulto , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Neoplasias Cutâneas , Adulto Jovem
20.
Hum Genet ; 134(7): 679-89, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25986438

RESUMO

Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. The aim here is to give an overview of the evidence for the importance of telomere length (TL) to the risk of common disease, considering the strengths and weaknesses of different epidemiological study designs. Methods for measuring TL are described, all of which are subject to considerable measurement error. TL declines with age and varies in relation to factors such as smoking and obesity. It is also highly heritable (estimated heritability of ~40 to 50%), and genome-wide studies have identified a number of associated genetic variants. Epidemiological studies have shown shorter TL to be associated with risk of a number of common diseases, including cardiovascular disease and some cancers. The relationship with cancer appears complex, in that longer telomeres are associated with higher risk of some cancers. Prospective studies of the relationship between TL and disease, where TL is measured before diagnosis, have numerous advantages over retrospective studies, since they avoid the problems of reverse causality and differences in sample handling, but they are still subject to potential confounding. Studies of the genetic predictors of TL in relation to disease risk avoid these drawbacks, although they are not without limitations. Telomere biology is of major importance to the risk of common disease, but the complexities of the relationship are only now beginning to be understood.


Assuntos
Doenças Cardiovasculares/metabolismo , Neoplasias/metabolismo , Obesidade/metabolismo , Fumar/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Doenças Cardiovasculares/genética , Humanos , Neoplasias/genética , Obesidade/genética , Fatores de Risco , Fumar/genética , Telômero/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...