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2.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
3.
Biol Psychiatry ; 85(11): 946-955, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30679032

RESUMO

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

4.
Mol Psychiatry ; 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617275

RESUMO

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

5.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
6.
Cancer Res ; 78(18): 5419-5430, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054336

RESUMO

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

7.
Genet Med ; 2018 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-29565421

RESUMO

PurposeBRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives.MethodsWe used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs).ResultsA total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort.ConclusionOur results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.Genetics in Medicine advance online publication, 22 March 2018; doi:10.1038/gim.2018.44.

8.
J Med Genet ; 55(6): 384-394, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29386252

RESUMO

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

9.
Breast Cancer Res Treat ; 167(1): 249-256, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28913729

RESUMO

PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial ß-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/genética , Cardiotoxicidade/genética , Flavoproteínas Transferidoras de Elétrons/genética , Adulto , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobreviventes de Câncer , Cardiotoxicidade/fisiopatologia , Exoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia
10.
Pharmacogenet Genomics ; 27(12): 445-453, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28961156

RESUMO

OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Exoma , Predisposição Genética para Doença , Coração/efeitos dos fármacos , Leucemia/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Receptores Acoplados a Proteínas-G/genética , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia/fisiopatologia , Masculino , Osteossarcoma/complicações , Sarcoma de Ewing/complicações
12.
JAMA ; 317(23): 2402-2416, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28632866

RESUMO

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação , Segunda Neoplasia Primária/genética , Neoplasias Ovarianas/genética , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Família , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Neoplasias Ovarianas/epidemiologia , Estudos Prospectivos , Medição de Risco , Fatores de Tempo
13.
Nat Genet ; 49(7): 1113-1119, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530674

RESUMO

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Assuntos
Artérias/patologia , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Aterosclerose/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Genótipo , Código das Histonas , Humanos , Masculino , Músculo Liso Vascular/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
14.
Nat Genet ; 48(10): 1151-1161, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618447

RESUMO

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos
15.
EBioMedicine ; 10: 150-63, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27515689

RESUMO

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.


Assuntos
Marcadores Genéticos , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Tolerância a Radiação/genética , Radioterapia/efeitos adversos , Idoso , Alelos , Estudos de Coortes , Terapia Combinada , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Resultado do Tratamento
16.
Eur J Hum Genet ; 22(11): 1330-3, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24549056

RESUMO

Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ≥70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Polipose Adenomatosa do Colo/complicações , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Adulto , Idoso , Neoplasias Colorretais/complicações , Neoplasias Colorretais/diagnóstico , Éxons , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Adulto Jovem
17.
Obesity (Silver Spring) ; 21(1): E137-42, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23505195

RESUMO

OBJECTIVE: Self-reported weight may underestimate measured weight. Researchers have tried to reduce the error using statistical models to predict weight from self-reported weight. We investigate whether deriving equations within separate BMI categories improves the prediction of weight compared with an equation derived regardless of an individual's BMI. DESIGN AND METHODS: The analysis included self-reported and measured data from 20,536 individuals participating in the EPIC-Norfolk study. In a derivation set (n = 15,381) two approaches were used to predict weight from self-reported weight: (1) using a linear regression model with measured weight as outcome and self-reported weight and age as predictors, and (2) using the same model fit separately within 3 strata defined by BMI (< 25, 25-30, ≥ 30 kg m(-2) ). The performance of these approaches was assessed in a validation set (n = 5,155). Measured weight was compared to self-reported weight and predicted weight. RESULTS: Self-reported weight underestimated measured weight (P < 0.0001): mean difference -1.2 ± 3.1 kg (men), -1.3 ± 2.5 kg (women). Underestimation was greater in obese participants (P < 0.0001). Predicted weight using approach 1 was not significantly different from measured weight (P < 0.05). However, in individuals with BMI < 25 kg m(-2) , weight was overestimated in men (0.90 ± 3.87 kg) and women (0.57 ± 2.06 kg), but underestimated in overweight (-0.29 ± 3.58, -0.20 ± 2.62 kg) and obese (-1.46 ± 5.05 kg, -0.73 ± 3.54 kg) men and women. CONCLUSIONS: Using separate prediction equations in strata of BMI did not further improve prediction of weight. In conclusion, predicted weight was closer to measured weight compared with self-reported weight, but using equations derived in strata of BMI did not further improve the prediction and are not recommended for prediction of weight.


Assuntos
Índice de Massa Corporal , Peso Corporal , Modelos Biológicos , Obesidade , Autorrelato , Idoso , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Sobrepeso , Valores de Referência , Reprodutibilidade dos Testes , Fatores Sexuais
18.
PLoS Genet ; 8(9): e1002894, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23028338

RESUMO

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , RecQ Helicases/genética , Deleção de Sequência/genética , Alelos , Exoma/genética , Éxons , Proteína do Grupo de Complementação C da Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Genoma Humano , Humanos , Linhagem , Polimorfismo Genético , RecQ Helicases/metabolismo , Análise de Sequência de DNA
19.
Genet Epidemiol ; 36(3): 274-91, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22714938

RESUMO

There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL-CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias-RB: -25% to -17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: -2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Heterozigoto , Modelos Genéticos , Mutação , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Testes Genéticos , Humanos , Funções Verossimilhança , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Adulto Jovem
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