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1.
Nat Commun ; 11(1): 5562, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144568

RESUMO

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.


Assuntos
Predisposição Genética para Doença , Característica Quantitativa Herdável , Tabagismo/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação/genética , Metanálise como Assunto , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
2.
Am J Epidemiol ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870973

RESUMO

Several statistical methods have been proposed for testing gene(G)-environment(E) interactions under additive risk models using genome-wide association study data. However, these approaches have strong assumptions on underlying genetic models such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aim to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose two sets of constraints for (i) the linear trend effect of genotype and (ii) the additive joint effects of G and E. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5- fold. We applied the proposed methods to examine gene-smoking interaction for lung cancer and gene-APOE*4 interaction for Alzheimer's disease, which identified two interactions between APOE*4 and loci MS4A and BIN1 at genome-wide significance that were replicated using independent data.

3.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

4.
JAMA Oncol ; 6(5): 724-734, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191290

RESUMO

Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures: The frequency of rare pathogenic or likely pathogenic genetic variants. Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.

5.
Nicotine Tob Res ; 22(6): 900-909, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.


Assuntos
Fumar Cigarros/genética , Marcadores Genéticos , Genoma Humano , Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único , Tabagismo/genética , Fumar Cigarros/epidemiologia , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Metanálise como Assunto , Tabagismo/epidemiologia , Estados Unidos/epidemiologia
6.
Int J Cancer ; 146(7): 1862-1878, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Transcriptoma , Linhagem Celular Tumoral , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
7.
Cancer Epidemiol ; 58: 25-32, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30445228

RESUMO

BACKGROUND: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. METHODS: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. RESULTS: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). CONCLUSIONS: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.


Assuntos
Adenocarcinoma/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adenocarcinoma/etiologia , Idoso , Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e Questionários
8.
Br J Haematol ; 181(3): 372-377, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29693246

RESUMO

In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two families with distinct heterozygous rare coding variants in POT1 (D224N and Y36H), both in a highly conserved region of the gene. POT1 D224N mutant did not bind to a single-stranded telomere oligonucleotide in vitro suggesting the mutation perturbs POT1's ability to bind to the telomeric G-rich overhang. Human HT1080 cells expressing POT1 D224N and lymphoblastoid cells carrying Y36H both showed increased telomere length and fragility in comparison to wild type cells. This strongly suggests that mutant POT1 causes chromosome instability and may play a role in lymphomagenesis in these families.


Assuntos
Instabilidade Cromossômica , Família , Mutação em Linhagem Germinativa , Doença de Hodgkin , Mutação de Sentido Incorreto , Proteínas de Ligação a Telômeros , Substituição de Aminoácidos , Linhagem Celular Tumoral , Feminino , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Telômero/genética , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
9.
Carcinogenesis ; 38(5): 541-551, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28383684

RESUMO

Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Metilação de DNA , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Neoplasias Pulmonares/patologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Fatores de Risco
10.
Hum Mol Genet ; 25(3): 620-9, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26732429

RESUMO

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Feminino , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Razão de Chances , Fumar
11.
Cancer Res ; 74(20): 5808-18, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25320178

RESUMO

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.


Assuntos
Cromossomos Humanos Par 19/genética , Ciclina E/genética , Proteínas Oncogênicas/genética , Neoplasias da Bexiga Urinária/genética , Estudos de Casos e Controles , Ciclina E/metabolismo , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Haplótipos , Células HeLa , Humanos , Proteínas Oncogênicas/metabolismo , Polimorfismo de Nucleotídeo Único , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
12.
Melanoma Res ; 24(5): 480-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25026000

RESUMO

Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16, p14, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFα), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFα (OR=0.81, 95% CI=0.69-0.95), hTERT (OR=0.90, 95% CI=0.82-0.99), and ALU (OR=1.56, 95% CI=1.02-2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM.


Assuntos
Metilação de DNA , Melanoma/sangue , Melanoma/genética , Nevo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Elementos Alu , Estudos de Casos e Controles , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Produtos do Gene env/genética , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/genética , Leucócitos Mononucleares/citologia , Elementos Nucleotídeos Longos e Dispersos , Masculino , Análise Multivariada , Proteína 1 Homóloga a MutL , Mutação , Nevo/fisiopatologia , Proteínas Nucleares/genética , Proteínas da Gravidez/genética , Receptor Tipo 1 de Melanocortina/genética , Fatores de Risco , Neoplasias Cutâneas , Telomerase/genética , Fator de Necrose Tumoral alfa/genética , Proteína Supressora de Tumor p14ARF/genética
13.
Front Genet ; 5: 53, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24672538

RESUMO

Copy number variations (CNVs) constitute a major source of genetic variations in human populations and have been reported to be associated with complex diseases. Methods have been developed for detecting CNVs and testing CNV associations in genome-wide association studies (GWAS) based on SNP arrays. Commonly used two-step testing procedures work well only for long CNVs while direct CNV association testing methods work only for recurrent CNVs. Assuming that short CNVs disrupting any part of a given genomic region increase disease risk, we developed a variable threshold exact test (VTET) for testing disease associations of CNVs randomly distributed in the genome using intensity data from SNP arrays. By extensive simulations, we found that VTET outperformed two-step testing procedures based on existing CNV calling algorithms for short CNVs and that the performance of VTET was robust to the length of the genomic region. In addition, VTET had a comparable performance with CNVtools for testing the association of recurrent CNVs. Thus, we expect VTET to be useful for testing disease associations of both recurrent and randomly distributed CNVs using existing GWAS data. We applied VTET to a lung cancer GWAS and identified a genome-wide significant region on chromosome 18q22.3 for lung squamous cell carcinoma.

14.
Carcinogenesis ; 35(6): 1267-75, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24523449

RESUMO

Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12-0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.


Assuntos
Alphapapillomavirus/genética , Neoplasias Pulmonares/etiologia , Infecções por Papillomavirus/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Prevalência , Integração Viral
15.
J Natl Cancer Inst ; 104(11): 840-54, 2012 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-22523397

RESUMO

BACKGROUND: Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. METHODS: A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. RESULTS: Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. CONCLUSIONS: To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.


Assuntos
Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Razão de Chances , Fatores de Risco
16.
Pigment Cell Melanoma Res ; 25(2): 243-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22225770

RESUMO

Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma.


Assuntos
Quimiocinas CXC/genética , Cromossomos Humanos Par 4/genética , Duplicação Gênica/genética , Predisposição Genética para Doença , Melanoma/genética , Neoplasias Cutâneas/genética , Adulto , DNA de Neoplasias/genética , Família , Feminino , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Adulto Jovem
17.
Carcinogenesis ; 32(4): 507-15, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21292647

RESUMO

Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12 214 cases and 47 721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.


Assuntos
Ligante CD30/genética , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto , Idoso , Apoptose , Linhagem Celular Tumoral , Feminino , Humanos , Antígeno Ki-1/fisiologia , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Risco , Texas
18.
Pigment Cell Melanoma Res ; 24(2): 345-51, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21324100

RESUMO

Oncogenic BRAF mutations are more frequent in cutaneous melanoma occurring at sites with little or moderate sun-induced damage than at sites with severe cumulative solar ultraviolet (UV) damage. We studied cutaneous melanomas from geographic regions with different levels of ambient UV radiation to delineate the relative effects of cumulative UV damage, age, and anatomic site on the frequency of BRAF mutations. We show that BRAF-mutated melanomas occur in a younger age group on skin without marked solar elastosis and less frequently affect the head and neck area, compared to melanomas without BRAF mutations. The findings indicate that BRAF-mutated melanomas arise early in life at low cumulative UV doses, whereas melanomas without BRAF mutations require accumulation of high UV doses over time. The effect of anatomic site on the mutation spectrum further suggests regional differences among cutaneous melanocytes.


Assuntos
Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Pele/patologia , Pele/efeitos da radiação , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Cutâneas/patologia , Luz Solar , Raios Ultravioleta
19.
J Invest Dermatol ; 131(2): 480-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21085193

RESUMO

The presence of recurrent high-risk mutations in cyclin-dependent kinase inhibitor 2A/cyclin-dependent kinase 4 (CDKN2A/CDK4) among melanoma-prone families suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. To this end, we have developed a multiplex bead-based assay for high-throughput CDKN2A/CDK4 genotyping in the context of familial melanoma. Genomic DNA from 1,603 subjects (1,005 in training set and 598 in validation set) were amplified by multiplex PCR using five CDKN2A/CDK4 primer sets followed by multiplex allele-specific primer extension for 39 distinct germline variants. The products were then sorted and analyzed using the Luminex xMAP system. Genotypes were compared with previously determined sequence data. In the Toronto training cohort, all 145 samples with known variants were detected by the bead assay (100% concordance). Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77%). Overall, the bead assay correctly genotyped 1,540/1,603 (96.07%) of all individuals in the study and 1,540/1,545 (99.68%) of individuals whose variants were represented in the probe set. Out of a total of 62,517 allelic calls, 62,512 (99.99%) were correctly assigned. The multiplex bead-based assay is an accurate method for genotyping CDKN2A/CDK4 variants and is potentially useful in genotyping low-to-moderate melanoma risk single-nucleotide polymorphisms.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Cutâneas/genética , Alelos , DNA de Neoplasias/genética , Genótipo , Humanos , Melanoma/diagnóstico , Microesferas , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico
20.
Genet Epidemiol ; 32(7): 638-46, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18454494

RESUMO

Studies to detect genetic association with disease can be family-based, often using families with multiple affected members, or population based, as in population-based case-control studies. If data on both study types are available from the same population, it is useful to combine them to improve power to detect genetic associations. Two aspects of the data need to be accommodated, the sampling scheme and potential residual correlations among family members. We propose two approaches for combining data from a case-control study and a family study that collected families with multiple cases. In the first approach, we view a family as the sampling unit and specify the joint likelihood for the family members using a two-level mixed effects model to account for random familial effects and for residual genetic correlations among family members. The ascertainment of the families is accommodated by conditioning on the ascertainment event. The individuals in the case-control study are treated as families of size one, and their unconditional likelihood is combined with the conditional likelihood for the families. This approach yields subject specific maximum likelihood estimates of covariate effects. In the second approach, we view an individual as the sampling unit. The sampling scheme is accommodated using two-phase sampling techniques, marginal covariate effects are estimated, and correlations among family members are accounted for in the variance calculations. The models are compared in simulations. Data from a case-control and a family study from north-eastern Italy on melanoma and a low-risk melanoma-susceptibility gene, MC1R, are used to illustrate the approaches.


Assuntos
Estudos de Casos e Controles , Projetos de Pesquisa , Simulação por Computador , Saúde da Família , Feminino , Predisposição Genética para Doença , Variação Genética , Genética , Humanos , Itália , Funções Verossimilhança , Masculino , Melanoma/genética , Modelos Genéticos , Modelos Estatísticos
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