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1.
IUBMB Life ; 73(2): 328-340, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33368980

RESUMO

Cancer seriously impairs human health and survival. Many perturbations, such as increased oxidative stress, pathogen infection, and inflammation, promote the accumulation of DNA mutations, and ultimately lead to carcinogenesis. Tea is one of the most highly consumed beverages worldwide and has been linked to improvements in human health. Tea contains many active components, including tea polyphenols, tea polysaccharides, L-theanine, tea pigments, and caffeine among other common components. Several studies have identified components in tea that can directly or indirectly reduce carcinogenesis with some being used in a clinical setting. Many previous studies, in vitro and in vivo, have focused on the mechanisms that functional components of tea utilized to protect against cancer. One particular mechanism that has been well described is an improvement in antioxidant capacity seen with tea consumption. However, other mechanisms, including anti-pathogen, anti-inflammation and alterations in cell survival pathways, are also involved. The current review focuses on these anti-cancer mechanisms. This will be beneficial for clinical utilization of tea components in preventing and treating cancer in the future.

2.
BMC Med Genomics ; 13(1): 162, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126877

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have proven successful in predicting genetic risk of disease using single-locus models; however, identifying single nucleotide polymorphism (SNP) interactions at the genome-wide scale is limited due to computational and statistical challenges. We addressed the computational burden encountered when detecting SNP interactions for survival analysis, such as age of disease-onset. To confront this problem, we developed a novel algorithm, called the Efficient Survival Multifactor Dimensionality Reduction (ES-MDR) method, which used Martingale Residuals as the outcome parameter to estimate survival outcomes, and implemented the Quantitative Multifactor Dimensionality Reduction method to identify significant interactions associated with age of disease-onset. METHODS: To demonstrate efficacy, we evaluated this method on two simulation data sets to estimate the type I error rate and power. Simulations showed that ES-MDR identified interactions using less computational workload and allowed for adjustment of covariates. We applied ES-MDR on the OncoArray-TRICL Consortium data with 14,935 cases and 12,787 controls for lung cancer (SNPs = 108,254) to search over all two-way interactions to identify genetic interactions associated with lung cancer age-of-onset. We tested the best model in an independent data set from the OncoArray-TRICL data. RESULTS: Our experiment on the OncoArray-TRICL data identified many one-way and two-way models with a single-base deletion in the noncoding region of BRCA1 (HR 1.24, P = 3.15 × 10-15), as the top marker to predict age of lung cancer onset. CONCLUSIONS: From the results of our extensive simulations and analysis of a large GWAS study, we demonstrated that our method is an efficient algorithm that identified genetic interactions to include in our models to predict survival outcomes.

3.
Nat Commun ; 11(1): 2220, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393777

RESUMO

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.


Assuntos
Adenocarcinoma/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias Pulmonares/genética , Idoso , Alelos , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA-Seq , Fatores de Risco
4.
BMC Genet ; 20(1): 85, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718536

RESUMO

BACKGROUND: Over the relatively short history of Genome Wide Association Studies (GWASs), hundreds of GWASs have been published and thousands of disease risk-associated SNPs have been identified. Summary statistics from the conducted GWASs are often available and can be used to identify SNP features associated with the level of GWAS statistical significance. Those features could be used to select SNPs from gray zones (SNPs that are nominally significant but do not reach the genome-wide level of significance) for targeted analyses. METHODS: We used summary statistics from recently published breast and lung cancer and scleroderma GWASs to explore the association between the level of the GWAS statistical significance and the expression quantitative trait loci (eQTL) status of the SNP. Data from the Genotype-Tissue Expression Project (GTEx) were used to identify eQTL SNPs. RESULTS: We found that SNPs reported as eQTLs were more significant in GWAS (higher -log10p) regardless of the tissue specificity of the eQTL. Pan-tissue eQTLs (those reported as eQTLs in multiple tissues) tended to be more significant in the GWAS compared to those reported as eQTL in only one tissue type. eQTL density in the ±5 kb adjacent region of a given SNP was also positively associated with the level of GWAS statistical significance regardless of the eQTL status of the SNP. We found that SNPs located in the regions of high eQTL density were more likely to be located in regulatory elements (transcription factor or miRNA binding sites). When SNPs were stratified by the level of statistical significance, the proportion of eQTLs was positively associated with the mean level of statistical significance in the group. The association curve reaches a plateau around -log10p ≈ 5. The observed associations suggest that quasi-significant SNPs (10- 5 < p < 5 × 10- 8) and SNPs at the genome wide level of statistical significance (p < 5 × 10- 8) may have a similar proportions of risk associated SNPs. CONCLUSIONS: The results of this study indicate that the SNP's eQTL status, as well as eQTL density in the adjacent region are positively associated with the level of statistical significance of the SNP in GWAS.


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Escleroderma Sistêmico/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Modelos Estatísticos , Especificidade de Órgãos , Elementos Reguladores de Transcrição
5.
Int J Mol Sci ; 20(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652732

RESUMO

Cancer is a worldwide epidemic and represents a major threat to human health and survival. Reactive oxygen species (ROS) play a dual role in cancer cells, which includes both promoting and inhibiting carcinogenesis. Tea remains one of the most prevalent beverages consumed due in part to its anti- or pro-oxidative properties. The active compounds in tea, particularly tea polyphenols, can directly or indirectly scavenge ROS to reduce oncogenesis and cancerometastasis. Interestingly, the excessive levels of ROS induced by consuming tea could induce programmed cell death (PCD) or non-PCD of cancer cells. On the basis of illustrating the relationship between ROS and cancer, the current review discusses the composition and efficacy of tea including the redox-relative (including anti-oxidative and pro-oxidative activity) mechanisms and their role along with other components in preventing and treating cancer. This information will highlight the basis for the clinical utilization of tea extracts in the prevention or treatment of cancer in the future.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinogênese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Chá/química , Animais , Carcinogênese/metabolismo , Humanos , Oxirredução , Extratos Vegetais/farmacologia
6.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

7.
Bioinformatics ; 35(17): 2891-2898, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649252

RESUMO

MOTIVATION: Integration of multiple genetic sources for copy number variation detection (CNV) is a powerful approach to improve the identification of variants associated with complex traits. Although it has been shown that the widely used change point based methods can increase statistical power to identify variants, it remains challenging to effectively detect CNVs with weak signals due to the noisy nature of genotyping intensity data. We previously developed modSaRa, a normal mean-based model on a screening and ranking algorithm for copy number variation identification which presented desirable sensitivity with high computational efficiency. To boost statistical power for the identification of variants, here we present a novel improvement that integrates the relative allelic intensity with external information from empirical statistics with modeling, which we called modSaRa2. RESULTS: Simulation studies illustrated that modSaRa2 markedly improved both sensitivity and specificity over existing methods for analyzing array-based data. The improvement in weak CNV signal detection is the most substantial, while it also simultaneously improves stability when CNV size varies. The application of the new method to a whole genome melanoma dataset identified novel candidate melanoma risk associated deletions on chromosome bands 1p22.2 and duplications on 6p22, 6q25 and 19p13 regions, which may facilitate the understanding of the possible roles of germline copy number variants in the etiology of melanoma. AVAILABILITY AND IMPLEMENTATION: http://c2s2.yale.edu/software/modSaRa2 or https://github.com/FeifeiXiaoUSC/modSaRa2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Alelos , Interpretação Estatística de Dados , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade , Software
8.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
9.
Nat Commun ; 9(1): 3221, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104567

RESUMO

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.


Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
10.
EBioMedicine ; 32: 93-101, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29859855

RESUMO

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10-9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.


Assuntos
Adenocarcinoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373

RESUMO

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
12.
Oncotarget ; 8(54): 92420-92430, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190927

RESUMO

Rotavirus can lead to decreasing gut barrier function and diarrhea of children and young animals. Apple pectic oligosaccharide treatment reduced diarrhea in rotavirus-infected piglets. This study was conducted to explore whether apple pectic oligosaccharide administration could protect gut barrier function of piglets against rotavirus infection. A total of 28 crossbred weaned barrows were allotted into 2 treatments fed the diets supplementing 0 and 200 mg/kg apple pectic oligosaccharide. Half of pigs in each diet treatment were challenged by rotavirus on d 15. The whole duration of this experiment is 18 days. Rotavirus challenge increased average diarrhea index, and impaired microbiota in cecal digesta, and histology, expressions of tight-junction proteins, mucins and glucagon like peptide-2 concentrations, antioxidant capacity, endoplasmic reticulum stress, autophagy and apoptosis in jejunal mucosa of piglets. However, dietary apple pectic oligosaccharide supplementation relieved effects of rotavirus challenge on diarrhea, gut health, and antioxidant capacity, endoplasmic reticulum stress, autophagy and apoptosis of jejunal mucosa in piglets. These results suggest that apple pectic oligosaccharide administration can prevent diarrhea and damage of gut barrier function via improving antioxidant capacity that might reduce endoplasmic reticulum stress, autophagy and apoptosis of intestinal epithelial cells in rotavirus-infected piglets.

13.
Nat Genet ; 49(7): 1126-1132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604730

RESUMO

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


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fumar/epidemiologia , Homeostase do Telômero/genética
14.
J Am Soc Nephrol ; 28(8): 2311-2321, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28360221

RESUMO

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.


Assuntos
Loci Gênicos , Plasma/química , Simportadores de Sódio-Bicarbonato/genética , Sódio/análise , Fatores de Transcrição/genética , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/genética , Idoso , Grupos de Populações Continentais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar
15.
Cancer Epidemiol Biomarkers Prev ; 26(1): 126-135, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27697780

RESUMO

BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.


Assuntos
Predisposição Genética para Doença/epidemiologia , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Genótipo , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Prevalência , Prognóstico , Medição de Risco , Seleção Genética
16.
Clin Cancer Res ; 23(2): 399-406, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27435399

RESUMO

PURPOSE: We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. EXPERIMENTAL DESIGN: Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane-related functions. RESULTS: There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%). CONCLUSIONS: Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399-406. ©2016 AACR.


Assuntos
Vacinas Anticâncer/administração & dosagem , Terapia Baseada em Transplante de Células e Tecidos , Neoplasias Colorretais/terapia , Imunoterapia , Proteínas de Membrana/sangue , Idoso , Vacinas Anticâncer/imunologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Serina-Treonina Quinases TOR/genética
17.
Bioinformatics ; 33(4): 561-563, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28035028

RESUMO

Motivation: Checking concordance between reported sex and genotype-inferred sex is a crucial quality control measure in genome-wide association studies (GWAS). However, limited insights exist regarding the true accuracy of software that infer sex from genotype array data. Results: We present seXY, a logistic regression model trained on both X chromosome heterozygosity and Y chromosome missingness, that consistently demonstrated >99.5% sex inference accuracy in cross-validation for 889 males and 5,361 females enrolled in prostate cancer and ovarian cancer GWAS. Compared to PLINK, one of the most popular tools for sex inference in GWAS that assesses only X chromosome heterozygosity, seXY achieved marginally better male classification and 3% more accurate female classification. Availability and Implementation: https://github.com/Christopher-Amos-Lab/seXY. Contact: Christopher.I.Amos@dartmouth.edu. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Cromossomos Humanos , Estudo de Associação Genômica Ampla/métodos , Cromossomos Sexuais , Análise para Determinação do Sexo/métodos , Software , Feminino , Humanos , Masculino , Controle de Qualidade
18.
Nat Genet ; 48(12): 1544-1550, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749845

RESUMO

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.


Assuntos
Marcadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Neoplasias Bucais/genética , Infecções por Papillomavirus/genética , Neoplasias Faríngeas/genética , Idoso , Estudos de Casos e Controles , Feminino , Antígenos HLA , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Boca/metabolismo , Boca/patologia , Boca/virologia , Neoplasias Bucais/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Neoplasias Faríngeas/virologia
19.
Oncol Rep ; 36(6): 3371-3378, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27779704

RESUMO

Osteosarcoma (OS) is an aggressive malignant tumor that is mesenchymal in origin with a very low 5-year survival rate, particularly in the patients with locally advanced or metastatic tumors and recurrent disease. MicroRNAs (miRNAs) play a critical role in essential biological processes as cellular proliferation, differentiation and apoptosis in normal or cancer cells, including OS cells. In the present study, we aimed to investigate the role of miR-422a in OS. We demonstrated that miR-422a expression was significantly downregulated in OS tissues and cell lines compared with the normal controls. In addition, overexpression of miR-422a was able to inhibit cell proliferation and the ability of invasion, and enhance paclitaxel and cisplatin-mediated apoptosis in OS cells. Inversely, downregulation of miR-422a exhibited an opposite role. We further demonstrated that miR-422a directly targeted TGFß2 and regulated its expression and the activation of downstream molecules, smad2 and smad3 in OS cells. Thus, miR-422a/TGFß2/smad axis may be a potential target for OS treatment.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/genética , Fator de Crescimento Transformador beta2/genética , Regiões 3' não Traduzidas , Antineoplásicos/farmacologia , Sequência de Bases , Sítios de Ligação , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino/farmacologia , Expressão Gênica , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Paclitaxel/farmacologia , Interferência de RNA , Fator de Crescimento Transformador beta2/metabolismo
20.
BMC Bioinformatics ; 17: 122, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26961892

RESUMO

BACKGROUND: Identifying subpopulations within a study and inferring intercontinental ancestry of the samples are important steps in genome wide association studies. Two software packages are widely used in analysis of substructure: Structure and Eigenstrat. Structure assigns each individual to a population by using a Bayesian method with multiple tuning parameters. It requires considerable computational time when dealing with thousands of samples and lacks the ability to create scores that could be used as covariates. Eigenstrat uses a principal component analysis method to model all sources of sampling variation. However, it does not readily provide information directly relevant to ancestral origin; the eigenvectors generated by Eigenstrat are sample specific and thus cannot be generalized to other individuals. RESULTS: We developed FastPop, an efficient R package that fills the gap between Structure and Eigenstrat. It can: 1, generate PCA scores that identify ancestral origins and can be used for multiple studies; 2, infer ancestry information for data arising from two or more intercontinental origins. We demonstrate the use of FastPop using 2318 SNP markers selected from the genome based on high variability among European, Asian and West African (African) populations. We conducted an analysis of 505 Hapmap samples with European, African or Asian ancestry along with 19661 additional samples of unknown ancestry. The results from FastPop are highly consistent with those obtained by Structure across the 19661 samples we studied. The correlations of the results between FastPop and Structure are 0.99, 0.97 and 0.99 for European, African and Asian ancestry scores, respectively. Compared with Structure, FastPop is more efficient as it finished ancestry inference for 19661 samples in 16 min compared with 21-24 h required by Structure. FastPop also provided scores based on SNP weights so the scores of reference population can be applied to other studies provided the same set of markers are used. We also present application of the method for studying four continental populations (European, Asian, African, and Native American). CONCLUSIONS: We developed an algorithm that can infer ancestries on data involving two or more intercontinental origins. It is efficient for analyzing large datasets. Additionally the PCA derived scores can be applied to multiple data sets to ensure the same ancestry analysis is applied to all studies.


Assuntos
Algoritmos , Grupos de Populações Continentais/genética , Grupos Étnicos/genética , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Software , Teorema de Bayes , Genótipo , Projeto HapMap , Humanos
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