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1.
Cancer Res Commun ; 2(11): 1355-1371, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36643868

RESUMO

Prostate cell lines from diverse backgrounds are important to addressing disparities in prostate cancer (PCa) incidence and mortality rates among Black men. ACRJ-PC28 was developed from a transrectal needle biopsy and established via inactivation of the CDKN2A locus and simultaneous expression of human telomerase. Characterization assays included growth curve analysis, immunoblots, IHC, 3D cultures, immunofluorescence imaging, confocal microscopy, flow cytometry, WGS, and RNA-Seq. ACRJ-PC28 has been passaged more than 40 times in vitro over 10 months with a doubling time of 45 hours. STR profiling confirmed the novelty and human origin of the cell line. RNA-Seq confirmed the expression of prostate specific genes alpha-methylacyl-CoA racemase (AMACR) and NKX3.1 and Neuroendocrine specific markers synaptophysin (SYP) and enolase 2 (ENO2) and IHC confirmed the presence of AMACR. Immunoblots indicated the cell line is of basal-luminal type; expresses p53 and pRB and is AR negative. WGS confirmed the absence of exonic mutations and the presence of intronic variants that appear to not affect function of AR, p53, and pRB. RNA-Seq data revealed numerous TP53 and RB1 mRNA splice variants and the lack of AR mRNA expression. This is consistent with retention of p53 function in response to DNA damage and pRB function in response to contact inhibition. Soft agar anchorage-independent analysis indicated that the cells are transformed, confirmed by principal component analysis (PCA) where ACRJ-PC28 cells cluster alongside other PCa tumor tissues, yet was distinct. The novel methodology described should advance prostate cell line development, addressing the disparity in PCa among Black men.


Assuntos
Células Neuroendócrinas , Neoplasias da Próstata , Masculino , Humanos , Proteína Supressora de Tumor p53/genética , Células Neuroendócrinas/metabolismo , Neoplasias da Próstata/genética , Linhagem Celular , RNA Mensageiro , Região do Caribe
2.
Ethn Health ; 26(5): 659-675, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-30453751

RESUMO

Objective: Cancer mortality inequity among persons of African Ancestry is remarkable. Yet, Black inclusion in cancer biology research is sorely lacking and warrants urgent attention. Epidemiologic research linking African Ancestry and the African Diaspora to disease susceptibility and outcomes is critical for understanding the significant and troubling health disparities among Blacks. Therefore, in a cohort of diverse Blacks, this study examined differences in genetic ancestry informative markers (AIMs) in the DNA repair pathway and the cancer related biomarker 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).Methods: Participants completed a questionnaire and provided bio-specimens. AIMs in or around DNA repair pathway genes were analyzed to assess differences in minor allele frequency (MAF) across the 3 ethnic subgroups. NNAL concentration in urine was measured among current smokers.Results: To date the cohort includes 852 participants, 88.3% being Black. Of the 752 Blacks, 51.3% were US-born, 27.8% were Caribbean-born, and 19.6% were Africa-born. Current and former smokers represented 14.9% and 10.0%, respectively. US-born Blacks were more likely to be smokers and poor metabolizers of NNAL. Two-way hierarchical clustering revealed MAF of AIMs differed across the 3 ethnic subgroups.Conclusion: Our findings are consistent with the emerging literature demonstrating Black heterogeneity underscoring African Ancestry genetic subgroup differences - specifically relevant to cancer. Further investigations, with data harmonization and sharing, are urgently needed to begin to map African Ancestry cancer biomarkers as well as race, and race by place\region comparative biomarkers to inform cancer prevention and treatment in the era of precision medicine.


Assuntos
Etnicidade , Neoplasias , Migração Humana , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Philadelphia , Fumantes
3.
Prostate ; 80(15): 1365-1372, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32894795

RESUMO

BACKGROUND: Prostate cancer (PC) risk increases with African ancestry and a history of sexually transmitted infections (STIs). Also, single-nucleotide polymorphisms (SNPs) in toll-like receptor (TLR) genes influence PC risk. This pilot study explores interactions between STIs and TLR-related SNPs in relation to PC risk among Jamaican men. METHODS: This case-control study evaluates two TLR related SNPs in 356 Jamaican men (194 controls and 162 cases) with or without history of STIs using stepwise penalized logistic regression in multivariable analyses. RESULTS: Age (odds ratio [OR] = 1.08; 95% confidence interval [CI]: 1.04-1>.12; p < .001) and IRF3_rs2304206 GG genotype (OR = 0.47; 95% CI: 0.29-0<.78; p = .003) modulated PC risk in people with history of STIs. In the population with no history of STIs, resulting interactions between risk factors did not survive correction for multiple hypothesis testing. CONCLUSION: Overall, an interaction between the IFR3_rs2304206 variant and a history of exposure to STIs leads to greater decrease of PC risk than the presence of polymorphic genotype alone. These findings are suggestive and require further validation. Identification of gene variants along with detection of lifestyle behaviors may contribute to identification of men at a greater risk of PC development in the population.


Assuntos
Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etiologia , Infecções Sexualmente Transmissíveis/complicações , Receptores Toll-Like/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Jamaica , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco
4.
Carcinogenesis ; 38(2): 218-229, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28025390

RESUMO

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

5.
Cancer ; 123(5): 849-860, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27906459

RESUMO

BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase ß (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P < .001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P = .002). An association was observed between these eQTLs and OS (P < .037; FDR < 0.0363) as well as DFS (P = .018 to .0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society.


Assuntos
Carcinoma de Células Escamosas/genética , DNA Polimerase beta/genética , Estudos de Associação Genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Laríngeas/genética , Locos de Características Quantitativas/genética , Adulto , Negro ou Afro-Americano/genética , Idoso , Alelos , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genótipo , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Boca/patologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de RNA , Carcinoma de Células Escamosas de Cabeça e Pescoço , População Branca/genética
6.
Head Neck ; 38 Suppl 1: E867-72, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-25962720

RESUMO

BACKGROUND: Most studies on human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) have been performed on white Americans. Our study examined the incidence of HPV in an African American oropharyngeal SCC cohort and its survival. METHODS: African American patients with oropharyngeal SCC in a combined tumor registry were identified. HPV16 testing was performed by polymerase chain reaction (PCR) from DNA extracted from tumor blocks. The p16 staining was performed using standard immunohistochemistry. RESULTS: Forty-four patients were identified for analysis. Seventy-three percent of the tumors were HPV-positive. Only 39% of the patients who were HPV-positive were also p16-positive. Survival between all 3 tumor types, patients who tested HPV-positive/p16, HPV-positive/p16-positive, and HPV-negative/p16-negative was significantly different (p = .03). HPV/p16 status was significant on univariate and multivariate analysis. CONCLUSION: HPV oropharyngeal SCC is strongly present in this African American cohort. Two thirds of the patients who were HPV-positive were p16-negative. Greater study is needed to explain the high p16 negativity among this HPV-positive oropharyngeal SCC African American cohort. © 2015 Wiley Periodicals, Inc. Head Neck 38: E867-E872, 2016.


Assuntos
Carcinoma de Células Escamosas/etnologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Orofaríngeas/etnologia , Infecções por Papillomavirus/complicações , Adulto , Negro ou Afro-Americano , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , DNA Viral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Prevalência , Estudos Retrospectivos , Estados Unidos
7.
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
8.
Proc Natl Acad Sci U S A ; 102(3): 749-54, 2005 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-15640349

RESUMO

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas/fisiologia , Proto-Oncogenes/fisiologia , Fatores de Transcrição/fisiologia , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p18 , Inibidor de Quinase Dependente de Ciclina p27 , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína de Leucina Linfoide-Mieloide , Fases de Leitura Aberta , Regiões Promotoras Genéticas , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Ativação Transcricional , Transfecção , Proteínas Supressoras de Tumor/genética
9.
Cancer Cell ; 4(3): 197-207, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14522254

RESUMO

MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.


Assuntos
Sobrevivência Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Sistema Hematopoético/patologia , Proteínas de Fusão Oncogênica/metabolismo , Proto-Oncogenes , Fatores de Transcrição , Animais , Células da Medula Óssea/metabolismo , Células Cultivadas , Cricetinae , Cricetulus , Dimerização , Regulação Leucêmica da Expressão Gênica , Sistema Hematopoético/metabolismo , Histona-Lisina N-Metiltransferase , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Proteína Meis1 , Proteína de Leucina Linfoide-Mieloide , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Retroviridae , Transativadores/metabolismo
10.
Mol Cell ; 10(5): 1107-17, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12453418

RESUMO

MLL, the human homolog of Drosophila trithorax, maintains Hox gene expression in mammalian embryos and is rearranged in human leukemias resulting in Hox gene deregulation. How MLL or MLL fusion proteins regulate gene expression remains obscure. We show that MLL regulates target Hox gene expression through direct binding to promoter sequences. We further show that the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity is associated with Hox gene activation and H3 (Lys4) methylation at cis-regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates Hox expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas de Homeodomínio/metabolismo , Proto-Oncogenes , Fatores de Transcrição , Animais , Western Blotting , Linhagem Celular , Clonagem Molecular , Ilhas de CpG , DNA/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Primers do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Metilação , Camundongos , Modelos Genéticos , Proteína de Leucina Linfoide-Mieloide , Testes de Precipitina , Regiões Promotoras Genéticas , Ligação Proteica , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativação Transcricional , Transfecção , Regulação para Cima
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