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1.
J Exp Clin Cancer Res ; 37(1): 233, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236142

RESUMO

BACKGROUND: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. METHODS: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. RESULTS: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. CONCLUSIONS: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.


Assuntos
Carcinoma/tratamento farmacológico , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Animais , Carcinoma/genética , Carcinoma/patologia , Ciclina D1/sangue , Inibidor de Quinase Dependente de Ciclina p18/sangue , Variações do Número de Cópias de DNA/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Invest ; 36(6): 338-348, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30136875

RESUMO

Aneuploidy is a common feature of cancer cells and may contribute to cellular transformation and cancer development. In this study, we found that significant down-regulation of CDKN2A, CHEK2, CDCA8, TP53BP1, and CCNDBP1 led to chromosome imbalances in two diploid non-immortalized human cell lines; however, only CDKN2A inhibition enhanced cell proliferation and additionally up-regulated three cell cycle control genes: CDCA8, AURKA, and CCND. These results confirm that CDKN2A is a tumor suppressor gene driving human cancer development by inducing cell aneuploidy and cell cycle up-regulation.


Assuntos
Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Genes Supressores de Tumor , Aneuploidia , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Quinase do Ponto de Checagem 2/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
3.
Med Sci Monit ; 24: 4841-4850, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30002361

RESUMO

BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.


Assuntos
Adenoma/genética , DNA (Citosina-5-)-Metiltransferase 1/biossíntese , DNA (Citosina-5-)-Metiltransferases/biossíntese , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Hipofisárias/genética , Adenoma/enzimologia , Adenoma/metabolismo , Adenoma/patologia , Adulto , Antígenos CD , Caderinas/genética , Caderinas/metabolismo , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/enzimologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
Gynecol Oncol ; 150(3): 552-561, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29980281

RESUMO

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development. METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining. CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , DNA de Neoplasias/análise , Proteína Supressora de Tumor p53/genética , Neoplasias Vulvares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Everolimo/farmacologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 3/genética , Pessoa de Meia-Idade , Morfolinas/farmacologia , Mutação , PTEN Fosfo-Hidrolase/genética , Papillomaviridae , Infecções por Papillomavirus/complicações , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Proteína Smad4/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Vulvares/metabolismo , Neoplasias Vulvares/virologia , Tirosina Quinase 3 Semelhante a fms/genética
7.
Int J Hematol ; 108(3): 312-318, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29786757

RESUMO

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph- B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.


Assuntos
Variações do Número de Cópias de DNA/genética , Dosagem de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Deleção de Genes , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Fator de Transcrição Ikaros/genética , Janus Quinase 2/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Cell Mol Life Sci ; 75(20): 3817-3827, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29728713

RESUMO

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.


Assuntos
Proliferação de Células , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Animais , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p18/deficiência , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Giro Denteado/metabolismo , Giro Denteado/patologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese
9.
Mol Cells ; 41(5): 381-389, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29665672

RESUMO

ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p18/fisiologia , Proteínas de Neoplasias/fisiologia , Proteína Supressora de Tumor p14ARF/fisiologia , Apoptose , Divisão Celular , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p18/deficiência , Inibidor de Quinase Dependente de Ciclina p18/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Genes p16 , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-mdm2/fisiologia , Proteína Supressora de Tumor p14ARF/deficiência , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p53/fisiologia , Ubiquitinação
10.
Lipids Health Dis ; 17(1): 89, 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29673405

RESUMO

BACKGROUND: Coronary artery disease (CAD) remains the single most important cause of mortality worldwide. Many candidate and GWAS genetic variants have been identified in the recent years. In the current study, we selected six SNPs from various genes that have originally been identified in GWAS studies and examined the association of SNPs individually and as a genetic risk score (GRS) with CAD and blood lipid levels in the Pakistani subjects. METHODS: Six hundred twenty-four (404 cases and 219 controls) subjects were genotyped for variants rs10757274 in CDKN2A gene, rs17465637 in MIA3 gene, rs7025486 in DAB2IP gene, rs17228212 in SMAD3 gene, rs981887 in MRAS gene and rs1746048 in CXCL12 gene, by TaqMan and KASPar allele discrimination techniques. Serum lipid parameters were measured using commercially available kits. Statistical analyses were done using SPSS version 22. RESULTS: Individually, the single SNPs were not associated with CAD (p < 0.05). However, the combined GRS of 6 SNPs was significantly higher in cases than controls (4.89 ± 0.11 vs 4.58 ± 0.08, p = 0.024). Among blood lipids, GRS showed significant positive association with serum triglycerides levels (p = 0.022). CONCLUSION: The GRS was quantitatively associated with CAD risk and showed association with serum triglycerides levels, suggesting that the mechanism of these variants is likely to be in part at least through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Quimiocina CXCL12/genética , Doença da Artéria Coronariana/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad3/genética , Proteínas Ativadoras de ras GTPase/genética , Proteínas ras/genética , Adulto , Alelos , Translocador Nuclear Receptor Aril Hidrocarboneto/sangue , Estudos de Casos e Controles , Quimiocina CXCL12/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Inibidor de Quinase Dependente de Ciclina p18/sangue , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Risco , Proteína Smad3/sangue , Triglicerídeos/sangue , Proteínas Ativadoras de ras GTPase/sangue , Proteínas ras/sangue
11.
Acta Derm Venereol ; 98(7): 667-670, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29542807

RESUMO

Approximately 10% of all melanomas occur in subjects with a family history of melanoma. This retrospective follow-up study investigated the characteristics of patients with familial melanoma who made unscheduled visits to our pigmented lesions clinic, and the diagnosis of excised lesions. A total of 110 (9%) out of 1,267 patients made at least one unscheduled visit between May 2011 and February 2016. Histopathology was taken from 59 patients. Thirty-four naevi, 7 melanomas and 3 basal cell carcinomas were detected. All patients with melanoma were CDKN2A carriers and all melanomas were discovered at a very early stage. In this patient population it appears to be safe to limit visits to once or twice yearly, provided patients are easily able to make an unscheduled extra visit if they have a worrisome lesion. We recommend supporting patients' self-reliance by stimulating them to carry out self-examination of their skin.


Assuntos
Agendamento de Consultas , Carcinoma Basocelular/patologia , Melanoma/patologia , Nevo/patologia , Visita a Consultório Médico , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Basocelular/genética , Carcinoma Basocelular/cirurgia , Criança , Inibidor de Quinase Dependente de Ciclina p18/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Acesso aos Serviços de Saúde , Hereditariedade , Humanos , Masculino , Melanoma/genética , Melanoma/cirurgia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Nevo/genética , Nevo/cirurgia , Fenótipo , Estudos Retrospectivos , Autoexame , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia , Adulto Jovem
12.
BMC Res Notes ; 11(1): 181, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29544538

RESUMO

OBJECTIVES: Pathophysiological similarity exists between gestational diabetes mellitus (GDM) and type 2 diabetes mellitus with common genetic origin. Genetic liability for GDM in our population is still not researched. The goal was to reveal the genotypic and allele frequency differences of 2 single nucleotide polymorphisms (SNPs) namely, CDKAL1 (rs7754840) and CDKN2A/2B (rs10811661) between GDM pregnancies and normal pregnancies. We assessed them by real time polymerase chain reaction using Taqman® allelic discrimination assays. We included 47 GDM pregnant subjects and 51 normal glucose tolerance (NGT) pregnant women as controls. RESULTS: The genotype frequencies in the GDM group and the NGT group of rs7754840-GG/GC/CC were 6.4/15.7% (3/8), 55.3/45.1% (26/23) and 38.3/39.2% (18/20) respectively. Also, those of rs10811661-CC/CT/TT were 74.5/14.9/4.3% (38/7/2) and 80.9/19.6/5.9% (38/10/3) respectively. The allele frequencies in the GDM group and the NGT group of C/G and T/C were 66/34% (62/32), 61.8/38.2% (63/39) and 11.7/88.3% (11/83), 15.7/84.3% (16/86) respectively. There were no statistical differences between the two groups in allele frequencies and genotype frequencies (all P > 0.05). Non-significant association was seen in the two SNPs of CDKAL1 and CDKN2A/B genes with GDM. Further studies are essential to validate data.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Diabetes Gestacional/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , tRNA Metiltransferases/genética , Adolescente , Adulto , Alelos , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
13.
Medicine (Baltimore) ; 97(12): e0182, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29561434

RESUMO

BACKGROUND: Reduction of cyclin-dependent kinase inhibitor 2A (CDKN2A) (p16 and p14) expression through DNA methylation has been reported in prostate cancer (PCa). This meta-analysis was conducted to assess the difference of p16 and p14 methylation between PCa and different histological types of nonmalignant controls and the correlation of p16 or p14 methylation with clinicopathological features of PCa. METHODS: According to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, articles were searched in PubMed, Embase, EBSCO, Wanfang, and CNKI databases. The strength of correlation was calculated by the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Trial sequential analysis (TSA) was used to estimate the required population information for significant results. RESULTS: A total of 20 studies published from 1997 to 2017 were identified in this meta-analysis, including 1140 PCa patients and 530 cases without cancer. Only p16 methylation in PCa was significantly higher than in benign prostatic lesions (OR = 4.72, P = .011), but had a similar level in PCa and adjacent tissues or high-grade prostatic intraepithelial neoplasias (HGPIN). TSA revealed that this analysis on p16 methylation is a false positive result in cancer versus benign prostatic lesions (the estimated required information size of 5116 participants). p16 methylation was not correlated with PCa in the urine and blood. Besides, p16 methylation was not linked to clinical stage, prostate-specific antigen (PSA) level, and Gleason score (GS) of patients with PCa. p14 methylation was not correlated with PCa in tissue and urine samples. No correlation was observed between p14 methylation and clinical stage or GS. CDKN2A mutation and copy number alteration were not associated with prognosis of PCa in overall survival and disease-free survival. CDKN2A expression was not correlated with the prognosis of PCa in overall survival (492 cases) (P > .1), while CDKN2A expression was significantly associated with a poor disease-free survival (P < .01). CONCLUSION: CDKN2A methylation may not be significantly associated with the development, progression of PCa. Although CDKN2A expression had an unfavorable prognosis in disease-free survival. More studies are needed to confirm our results.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Metilação de DNA , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino
14.
J Mol Neurosci ; 64(3): 478-484, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29516350

RESUMO

DNA methylation may predispose to multiple sclerosis (MS), as aberrant methylation in the promoter regions across the genome seems to underlie several processes of MS. We have currently determined the methylation status of eight genes in relapsing-remitting MS patients. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was used to determine the status of 31 CpG islands, located across eight genes, in 33 healthy individuals and 66 MS patients (33 in relapse and 33 in remission). The methylation levels in the examined sites ranged from 0 to 31%. Methylation positivity for RUNX3 and CDKN2A differed significantly between MS patients and healthy controls. Maximum methylation in RUNX3, CDKN2A, SOCS1, and NEUROG1 genes was significantly different between patients and controls. Roc curves demonstrated that the appropriate cut-offs to distinguish patients from healthy controls were 2% for RUNX3 (OR 3.316, CI 1.207-9.107, p = 0.024) and 3% for CDKN2A (OR 3.077, CI 1.281-7.39, p = 0.018). No difference in methylation was observed between patients in relapse and patients in remission, in any of the genes examined. Methylation patterns of RUNX3 and CDKN2A may be able to distinguish between MS patients and healthy controls, but not between MS patients in relapse and in remission. Graphical Abstract Methylation patterns of RUNX3 and CDKN2A may be able to discriminate healthy individuals from MS patients.


Assuntos
Ilhas de CpG , Metilação de DNA , Esclerose Múltipla Recidivante-Remitente/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Proteínas do Tecido Nervoso/genética , Proteína 1 Supressora da Sinalização de Citocina/genética
15.
G3 (Bethesda) ; 8(5): 1475-1480, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29523635

RESUMO

Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n = 163) or with a positive family history (n = 133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used.In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counseling.


Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Proteínas de Ligação a Telômeros/genética , Idoso , Áustria , Inibidor de Quinase Dependente de Ciclina p18/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
16.
Acta Derm Venereol ; 98(5): 512-516, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29405243

RESUMO

Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families (17% CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma (SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area.


Assuntos
Biomarcadores Tumorais/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Variação Genética , Melanoma/genética , Mutação , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prevalência , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Espanha/epidemiologia
17.
Mol Vis ; 24: 143-152, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29430168

RESUMO

Purpose: Adenoid cystic carcinoma (ACC) in the lacrimal gland is a rare malignancy. P16 is encoded by the CDKN2A gene, which is recognized as a tumor suppressor due to its inactivation in many types of tumors. However, p16 overexpression is also linked to adverse tumor parameters. These contradictory observations have also been confirmed in ACCs in the salivary glands. Furthermore, evidence of human papilloma virus (HPV) infection is found in a proportion of ACCs in the salivary glands. P16 is often overexpressed in HPV-related squamous cell carcinoma in parallel. To our knowledge, the role of p16 and HPV in ACCs in the lacrimal gland is still unknown. Methods: Twenty-one ACCs in the lacrimal gland and ten matched healthy lacrimal glands were studied. P16 was detected with immunohistochemistry (IHC), and HPV was detected with in situ hybridization (ISH) and PCR in all cases. Other cell cycle proteins were also detected with IHC, including cyclin D1 and Ki67. The methylation status of the p16 promoter was detected with methylation-specific PCR (MSP) to further investigate the regulation of p16 expression. Results: The expression rates of p16 (47.6%, 10/21), cyclin D1 (100%, 21/21), and Ki67 (52.4%, 11/21) were increased in ACCs compared to healthy lacrimal glands (negative). The results showed p16 expression was limited to the inner ductal epithelial cells in the majority of the tubular and cribriform patterns. In solid ACCs, p16 was uniformly positive. HPV was negative in all 21 cases with ISH and PCR. P16 overexpression was associated with cyclin D1 overexpression (p=0.013). Only 13 cases were tested successfully with MSP. The expression rate of p16 methylation was 23.1% (3/13) of the ACCs. Compared with primary ACCs, recurrent ACCs showed higher p16, cyclin D1, and Ki67 expression (p=0.011, p=0.026, p=0.049, respectively). Conclusions: In summary, p16 overexpression was cell-type dependent in ACCs in the lacrimal gland, while HPV infection was negative. P16 overexpression was unrelated to HPV infection. The mechanism of p16 overexpression needs to be further investigated in ACCs in the lacrimal gland.


Assuntos
Carcinoma Adenoide Cístico/genética , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Neoplasias Oculares/genética , Regulação Neoplásica da Expressão Gênica , Antígeno Ki-67/genética , Adolescente , Adulto , Idoso , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Estudos de Casos e Controles , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Neoplasias Oculares/metabolismo , Neoplasias Oculares/mortalidade , Neoplasias Oculares/patologia , Feminino , Humanos , Antígeno Ki-67/metabolismo , Aparelho Lacrimal/metabolismo , Aparelho Lacrimal/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus , Análise de Sobrevida
18.
Diabetes ; 67(5): 872-884, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29432124

RESUMO

Genome-wide association studies link the CDKN2A/B locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14, p15, and p16; MTAP; and ANRIL, a long noncoding RNA. The goal of this study was to determine whether CDKN2A/B T2D risk SNPs impact locus gene expression, insulin secretion, or ß-cell proliferation in human islets. Islets from donors without diabetes (n = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (p14, p15, p16, MTAP, ANRIL, PCNA, KI67, and CCND2), insulin secretion (n = 61), and ß-cell proliferation (n = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: p14-p16-ANRIL, which increased with age, and MTAP-p15, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of ANRIL, but not p14, p15, p16, or MTAP, in age-dependent fashion, such that younger homozygous risk donors had higher ANRIL expression, equivalent to older donor levels. We identified several risk SNP combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk allele carriers at ANRIL coding SNP rs564398 had reduced ß-cell proliferation index. In conclusion, CDKN2A/B locus SNPs may impact T2D risk by modulating islet gene expression and ß-cell proliferation.


Assuntos
Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Polimorfismo de Nucleotídeo Único
19.
Gastroenterology ; 154(8): 2060-2063.e8, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29486199

RESUMO

Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.


Assuntos
Biomarcadores Tumorais/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Tumores Neuroendócrinos/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Montagem e Desmontagem da Cromatina/genética , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Sequenciamento Completo do Exoma
20.
Transl Behav Med ; 8(1): 29-43, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29385581

RESUMO

A CDKN2A/p16 mutation confers 28%-67% lifetime melanoma risk, a risk that may be moderated by ultraviolet radiation exposure. The aim of this study was to test whether melanoma genetic counseling and test disclosure conferred unique informational, motivational, or emotional benefits compared to family history-based counseling. Participants included were 114 unaffected members of melanoma-prone families, ages 16-69, 51.8% men, 65.8% with minor children or grandchildren. Carriers (n = 28) and noncarriers (n = 41) from families with a CDKN2A mutation were compared to no-test controls (n = 45) from melanoma-prone families without an identifiable CDKN2A mutation. All participants received equivalent counseling about melanoma risk and management; only CDKN2A participants received genetic test results. Using newly developed inventories, participants rated perceived costs and benefits for managing their own and their children's or grandchildren's melanoma risk 1 month and 1 year after counseling. Propensity scores controlled for baseline family differences. Compared to no-test controls, participants who received test results (carriers and noncarriers) reported feeling significantly more informed and prepared to manage their risk, and carriers reported greater motivation to reduce sun exposure. All groups reported low negative emotions about melanoma risk. Parents reported high levels of preparedness to manage children's risk regardless of group. Carrier parents reported greater (but moderate) worry about their children's risk than no-test control parents. Women, older, and more educated respondents reported greater informational and motivational benefits regardless of group. Genetic test results were perceived as more informative and motivating for personal sun protection efforts than equivalent counseling based on family history alone.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Aconselhamento Genético , Conhecimentos, Atitudes e Prática em Saúde , Melanoma/genética , Melanoma/psicologia , Comportamento de Redução do Risco , Adolescente , Adulto , Idoso , Feminino , Aconselhamento Genético/psicologia , Predisposição Genética para Doença , Testes Genéticos , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/psicologia , Adulto Jovem
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