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1.
Eur Urol ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32800727

RESUMO

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

2.
Cancer Epidemiol Biomarkers Prev ; 29(2): 434-442, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31826912

RESUMO

BACKGROUND: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. METHODS: Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. RESULTS: The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. CONCLUSIONS: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. IMPACT: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.

3.
J Thorac Oncol ; 13(10): 1483-1495, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981437

RESUMO

BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.


Assuntos
Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
4.
Carcinogenesis ; 39(9): 1135-1140, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29924316

RESUMO

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 9/genética , Humanos , Pulmão/patologia , Anamnese , Polimorfismo de Nucleotídeo Único/genética
5.
Genet Epidemiol ; 41(4): 297-308, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28211093

RESUMO

Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.


Assuntos
Algoritmos , Estudos de Associação Genética/métodos , Variação Genética , Simulação por Computador , Humanos , Modelos Genéticos , Tamanho da Amostra , Estatísticas não Paramétricas
6.
Genes (Basel) ; 8(1)2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28106732

RESUMO

Lung cancer is the deadliest cancer in the United States, killing roughly one of four cancer patients in 2016. While it is well-established that lung cancer is caused primarily by environmental effects (particularly tobacco smoking), there is evidence for genetic susceptibility. Lung cancer has been shown to aggregate in families, and segregation analyses have hypothesized a major susceptibility locus for the disease. Genetic association studies have provided strong evidence for common risk variants of small-to-moderate effect. Rare and highly penetrant alleles have been identified by linkage studies, including on 6q23-25. Though not common, some germline mutations have also been identified via sequencing studies. Ongoing genomics studies aim to identify additional high penetrance germline susceptibility alleles for this deadly disease.

7.
Am J Hum Genet ; 99(4): 877-885, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27666373

RESUMO

The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.


Assuntos
Doença/genética , Mutação de Sentido Incorreto/genética , Software , Área Sob a Curva , Análise Mutacional de DNA , Exoma/genética , Frequência do Gene , Humanos , Curva ROC
8.
Hum Genet ; 135(8): 923-38, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27262462

RESUMO

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Idoso , Frequência do Gene , Genótipo , Haplótipos/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Fatores de Risco
9.
Genet Epidemiol ; 40(6): 461-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27312771

RESUMO

Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work.


Assuntos
Modelos Genéticos , Teorema de Bayes , Estudos de Casos e Controles , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Sequência de DNA
10.
J Thorac Oncol ; 11(1): 52-61, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26762739

RESUMO

INTRODUCTION: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants. METHODS: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). RESULTS: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine ß-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). CONCLUSIONS: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Exoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Prognóstico , Doença Pulmonar Obstrutiva Crônica , Carcinoma de Pequenas Células do Pulmão/patologia , Fumar
11.
Hum Hered ; 82(1-2): 64-74, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28817824

RESUMO

OBJECTIVE: One of four American cancer patients dies of lung cancer. Environmental factors such as tobacco smoking are known to affect lung cancer risk. However, there is a genetic factor to lung cancer risk as well. Here, we perform parametric linkage analysis on family-based genotype data in an effort to find genetic loci linked to the disease. METHODS: 197 individuals from families with a high-risk history of lung cancer were recruited and genotyped using an Illumina array. Parametric linkage analyses were performed using an affected-only phenotype model with an autosomal dominant inheritance using a disease allele frequency of 0.01. Three types of analyses were performed: single variant two-point, collapsed haplotype pattern variant two-point, and multipoint analysis. RESULTS: Five novel genome-wide significant loci were identified at 18p11.23, 2p22.2, 14q13.1, 16p13, and 20q13.11. The families most informative for linkage were also determined. CONCLUSIONS: The 5 novel signals are good candidate regions, containing genes that have been implicated as having somatic changes in lung cancer or other cancers (though not in germ line cells). Targeted sequencing on the significant loci is planned to determine the causal variants at these loci.

12.
Am J Hum Genet ; 96(2): 301-8, 2015 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-25640678

RESUMO

PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.


Assuntos
Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Bases , Primers do DNA/genética , Exoma/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Razão de Chances , Linhagem , Análise de Sequência de DNA
13.
Int J Environ Res Public Health ; 11(8): 8383-98, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25153467

RESUMO

The underlying ethos of dbGaP is that access to these data by secondary data analysts facilitates advancement of science. NIH has required that genome-wide association study data be deposited in the Database of Genotypes and Phenotypes (dbGaP) since 2003. In 2013, a proposed updated policy extended this requirement to next-generation sequencing data. However, recent literature and anecdotal reports suggest lingering logistical and ethical concerns about subject identifiability, informed consent, publication embargo enforcement, and difficulty in accessing dbGaP data. We surveyed the International Genetic Epidemiology Society (IGES) membership about their experiences. One hundred and seventy five (175) individuals completed the survey, a response rate of 27%. Of respondents who received data from dbGaP (43%), only 32% perceived the application process as easy but most (75%) received data within five months. Remaining challenges include difficulty in identifying an institutional signing official and an overlong application process. Only 24% of respondents had contributed data to dbGaP. Of these, 31% reported local IRB restrictions on data release; an additional 15% had to reconsent study participants before depositing data. The majority of respondents (56%) disagreed that the publication embargo period was sufficient. In response, we recommend longer embargo periods and use of varied data-sharing models rather than a one-size-fits-all approach.


Assuntos
Bases de Dados como Assunto , Estudo de Associação Genômica Ampla , Disseminação de Informação/ética , Atitude , Humanos , Consentimento Livre e Esclarecido , Percepção , Inquéritos e Questionários
14.
Prostate ; 73(6): 614-23, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23060098

RESUMO

BACKGROUND: Prostate cancer is a complex multi-allelic disease and the most common malignancy in men. The incidence of prostate cancer in African American men is more than twice as high as that of any other race. Despite the high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. Although genomic copy number variations (CNVs) have been detected in prostate tumors, this is the first study describing germline CNVs in African American hereditary prostate cancer families. METHODS: Ten high-risk African American families with three or more affected individuals and with an early age of onset were recruited. From these families, 37 individuals, including 23 affected males, and 14 unaffected males, were selected for CNV analysis. Array comparative genomic hybridization was used to characterize germline CNVs unique to African American men with hereditary prostate cancer. RESULTS: Through common aberration analysis in affected family members; novel CNVs were identified at chromosomes 1p36.13 and 16q23.3. Differential analysis comparing affected and unaffected family members identified 9.4 kb duplication on chromosome 14q32.33 which segregate with prostate cancer patients in these high-risk families. CONCLUSIONS: The duplication at 14q32.33 encompasses IGHG3 gene which has been shown to have both significant gains in copy number as well as overexpression in prostate tumors in African Americans. These CNVs may represent a component of genetic predisposition which contributes to the high prevalence and mortality of prostate cancer in African American men.


Assuntos
Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Variações do Número de Cópias de DNA/genética , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Idoso , Animais , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 16 , Estudos de Coortes , Hibridização Genômica Comparativa , Saúde da Família , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estados Unidos/epidemiologia
15.
Hum Genet ; 132(1): 5-14, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23064873

RESUMO

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.


Assuntos
Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Substituição de Aminoácidos , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Agências Internacionais , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
16.
Prostate ; 72(9): 938-47, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22615067

RESUMO

BACKGROUND: In the United States, incidence of prostate cancer in African American men is more than twice than that of any other race. Thus far, numerous disease susceptibility loci have been identified for this cancer but definite locus-specific information is not yet established due to the tremendous amount of genetic and disease heterogeneity; additionally, despite high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. METHODS: In order to identify the susceptible locus (loci) for prostate cancer in African Americans, we have performed linkage analyses on members of 15 large high-risk families. Specifically, these families were recruited from Louisiana and represent a uniquely admixed African American population exclusive to Southern Louisiana. In addition to geographical constraints, these families were clinically homogeneous creating a well-characterized collection of large pedigrees. The families were genotyped with Illumina Infinium II SNP HumanLinkage-12 panel and extensive demographic and clinical information was documented from the hospital pathological reports and family interviews. RESULTS: We identified two novel regions, 12q24 and 2p16, with suggestive evidence of linkage under the dominant model of inheritance. CONCLUSIONS: This is the first time that chromosome 12q24 (HLOD = 2.21) and 2p16 (HLOD = 1.97) has been shown to be associated with prostate cancer in high-risk African American families. These results provide insight to prostate cancer in an exceptional, well-characterized African American population, and illustrate the significance of utilizing large unique, but homogenous pedigrees.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 2/genética , Ligação Genética/genética , Neoplasias da Próstata/genética , Afro-Americanos/etnologia , Idoso , Medicina Baseada em Evidências/métodos , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Louisiana/etnologia , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia
17.
Cancer Res ; 70(8): 3128-35, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20395203

RESUMO

A common variant on chromosomal region 15q24-25.1, marked by rs1051730, was found to be associated with lung cancer risk. Here, we attempted to confirm the second variant on 15q24-25.1 in several large sporadic lung cancer populations and determined what percentage of additional risk for lung cancer is due to the genetic effect of the second variant. SNPs rs1051730 and rs481134 were genotyped in 2,818 lung cancer cases and 2,766 controls from four populations. Joint analysis of these two variants (rs1051730 and rs481134) on 15q24-25.1 identified three major haplotypes (G_T, A_C, and G_C) and provided stronger evidence for association of 15q24-25.1 with lung cancer (P = 9.72 x 10(-9)). These two variants represent three levels of risk associated with lung cancer. The most common haplotype G_T is neutral; the haplotype A_C is associated with increased risk for lung cancer with 5.0% higher frequency in cases than in controls [P = 1.68 x 10(-7); odds ratio (OR), 1.24; 95% confidence interval (95% CI), 1.14-1.35]; whereas the haplotype G_C is associated with reduced risk for lung cancer with 4.4% lower frequency in cases than in controls (P = 7.39 x 10(-7); OR, 0.80; 95% CI, 0.73-0.87). We further showed that these two genetic variants on 15q24-25.1 independently influence lung cancer risk (rs1051730: P = 4.42 x 10(-11); OR, 1.60; 95% CI, 1.46-1.74; rs481134: P = 7.01 x 10(-4); OR, 0.81; 95% CI, 0.72-0.92). The second variant on 15q24-25.1, marked by rs481134, explains an additional 13.2% of population attributable risk for lung cancer.


Assuntos
Cromossomos Humanos Par 15 , Regulação Neoplásica da Expressão Gênica , Variação Genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Afro-Americanos , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Haplótipos , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Estatísticos , Razão de Chances , Análise de Regressão , Risco
18.
Cancer Res ; 70(6): 2359-67, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20215501

RESUMO

Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (>or=40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers.


Assuntos
Cromossomos Humanos Par 6 , Neoplasias Pulmonares/genética , Fumar/genética , Feminino , Ligação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Fumar/efeitos adversos
19.
Cancer Epidemiol Biomarkers Prev ; 19(2): 517-24, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20142248

RESUMO

BACKGROUND: Genetic factors play important roles in lung cancer susceptibility. In this study, we replicated the association of 5p15.33 and 6p21.33 with familial lung cancer. Taking into account the previously identified genetic susceptibility variants on 6q23-25/RGS17 and 15q24-25.1, we further determined the cumulative association of these four genetic regions and the population attributable risk percent of familial lung cancer they account for. METHODS: One hundred ninety-four case patients and 219 cancer-free control subjects from the Genetic Epidemiology of Lung Cancer Consortium were used for the association analysis. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Single nucleotide polymorphisms (SNP) on chromosomal regions 5p15.33, 6p21.33, 6q23-25/RGS17, and 15q24-25.1 were assessed for their associations with familial lung cancer. The cumulative association of the four chromosomal regions with familial lung cancer was evaluated with the use of a linear logistic model. Population attributable risk percent was calculated for each SNP using risk ratio. RESULTS: SNP rs31489 showed the strongest evidence of familial lung cancer association on 5p15.33 (P = 2 x 10(-4); odds ratio, 0.57; 95% confidence interval, 0.42-0.77), whereas rs3117582 showed a weak association on 6p21.33 (P = 0.09; odds ratio, 1.47; 95% confidence interval, 0.94-2.31). Analysis of a combination of SNPs from the four regions provided a stronger cumulative association with familial lung cancer (P = 6.70 x 10(-6)) than any individual SNPs. The risk of lung cancer was increased to 3- to 11-fold among those subjects who had at least one copy of risk allele at each region compared with subjects without any of the risk factors. These four genetic regions contribute to a total of 34.6% of familial lung cancer in smokers. CONCLUSIONS: The SNPs in four chromosomal regions have a cumulative and significant association with familial lung cancer and account for about one-third of the population attributable risk for familial lung cancer.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
20.
Asian J Androl ; 12(3): 336-43, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20173765

RESUMO

Race, family history and age are the unequivocally accepted risk factors for prostate cancer (PCa). Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR (A1675T) (T559S) substitution mutation in the DNA-binding domain in three PCa-affected members of an African-American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR (T559S) mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR (A1675T) allele to early-onset and/or familial PCa in African Americans.


Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Mutação de Sentido Incorreto , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Adenocarcinoma/etnologia , Adenocarcinoma/metabolismo , Afro-Americanos/etnologia , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Saúde da Família/etnologia , Feminino , Humanos , Louisiana/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo
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