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1.
Nat Commun ; 12(1): 808, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547292

RESUMO

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , /imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia
2.
BMC Med Genet ; 21(1): 205, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066747

RESUMO

BACKGROUND: CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. METHODS: We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14ARF, p16INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/µL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. RESULTS: The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14ARF, p16INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. CONCLUSIONS: Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.


Assuntos
Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Mucosa Gástrica/metabolismo , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Antígenos CD/genética , Caderinas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas Quinases Associadas com Morte Celular/genética , Feminino , Mucosa Gástrica/microbiologia , Frequência do Gene , Genótipo , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
3.
BMC Med Genet ; 21(1): 201, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046033

RESUMO

BACKGROUND: CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). METHODS: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. RESULTS: We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26-5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22-6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25-6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p = 0.022). CONCLUSIONS: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.


Assuntos
Colite Ulcerativa/genética , Ilhas de CpG/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Colite Ulcerativa/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
4.
Anticancer Res ; 40(11): 6355-6366, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109573

RESUMO

BACKGROUND/AIM: p16 and PTEN are tumor suppressor genes. Loss of these molecules in oral squamous cell carcinoma (OSCC) has been studied worldwide. In this study, we explored whether p16 cooperates with inactive PTEN during the pathogenesis of OSCC, especially in regard to tumor aggressiveness and proliferation. MATERIALS AND METHODS: Immunocytochemistry and western blot analysis were used to examine the levels of p16 and PTEN. Sequencing analysis was performed to identify mutations in the PTEN gene and HPV infection. Fluorescence in situ hybridization was used to examine the presence of the PTEN locus. RESULTS: PTEN analysis showed high positivity in T4 samples. HPV-positive tumors correlated with tabagism, tumor size 3 and 4, disease stages 3 and 4, presence of lymph node metastasis (N1) and poor differentiation. Immunoexpression of p16 was strongly correlated with the presence of HPV. CONCLUSION: PTEN demonstrated a higher reactivity in advanced disease stages and p16 was strongly associated with HPV. Viral presence decreases tumor aggressiveness. Patients with advanced stage lesions demonstrated lower survival rate.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia
5.
Zhonghua Zhong Liu Za Zhi ; 42(8): 644-647, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867455

RESUMO

Objective: To explore the application value of lung cancer-related gene methylation in lung cancer diagnosis. Methods: Sixty patients with lung cancer underwent surgery were selected as the case group, and 65 patients with benign lung lesions treated in the same period were recruited as the control group. The methylation levels of lung cancer-related genes including dying-associated protein kinase (DAPK), O-6-methylguanine-DNA methyltransferase (MGMT), APC gene promoter 1A (APC1A) and epithelial mucoprotein gene (ECAD) in the blood samples of two groups of patients were analyzed by methylated PCR-specific method. The relationship between methylation of lung cancer-related genes and lung cancer was analyzed and its diagnostic value in lung cancer was evaluated. Results: The methylation detection rates of DAPK, MGMT, APC1A and ECAD in the case group were 68.3%, 68.3%, 63.3% and 65.0%, respectively, all higher than those of the control group (all P<0.05). The multivariate Logistic regression analysis showed that DAPK (OR=0.709), MGMT (OR=0.793), APC1A (OR=0.163), and ECAD (OR=2.047) were all independent influencing factors for lung cancer (all P<0.05). Analysis of the receiver operating characteristic curve showed that, the area under the curve (AUC) of DAPK, MGMT, APC1A and ECAD methylation test for lung cancer predicting were 0.623, 0.680, 0.620 and 0.648, respectively, while the AUC of the combined four gene methylation for lung cancer predicting was 0.829, higher than the AUC of each gene (all P<0.05). Conclusion: The combined methylation detection of multiple lung cancer related genes can improve the diagnostic value of lung cancer, contribute to the early diagnosis of lung cancer, and have potentially clinical application value.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Proteínas Quinases Associadas com Morte Celular/genética , Neoplasias Pulmonares/diagnóstico , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas/genética , Estudos de Casos e Controles , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética
6.
PLoS One ; 15(9): e0238497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986729

RESUMO

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 ("tumor-only" mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Idoso , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , DNA Viral/genética , Gerenciamento de Dados , Bases de Dados de Ácidos Nucleicos , Testes Diagnósticos de Rotina , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/virologia , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Transcriptoma
7.
Adv Exp Med Biol ; 1255: 133-142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949396

RESUMO

Lung cancer is the leading cause of death from cancer in China. The lack of early screening technologies makes most patients to be diagnosed at advanced stages with a poor prognosis which often miss the best treatment opportunities. Thus, identifying biomarkers for minimally invasive detection and prognosis of early stage disease is urgently needed. Genetic and epigenetic alterations that promote tumorigenesis and metastasis exist in multiple cancers. These aberrant alterations usually represent early events in cancer progression suggesting their potential applications as a biomarker for cancer prediction. Studies have shown that DNA methylation is one of the key factors in progression of lung cancer. P16 promoter methylation is one of the most common epigenetic change plays a key role in lung cancer. In this review, we highlight the p16 gene methylation and its clinical significance in lung cancer.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Genes p16 , Neoplasias Pulmonares/genética , Humanos , Regiões Promotoras Genéticas
8.
Am J Surg Pathol ; 44(10): 1308-1321, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739935

RESUMO

Neuroendocrine carcinoma (NEC) is an aggressive malignant tumor that rarely arises from the gallbladder. Here, we investigated the clinicopathologic and immunohistochemical characteristics of 34 NECs of the gallbladder. The patients were predominantly women (68%) with a median age of 63 years (range, 37 to 82 y). NECs frequently occurred in the fundus (44%) as mass-forming lesions (66%). Histologically, 17 tumors were of small cell type, and another 17 were of large cell type. Twenty-three cases (68%) were associated with biliary intraepithelial neoplasia (38%) and intracholecystic papillary neoplasm (29%). The majority of tumors exhibited a diffuse growth pattern (74%), followed by organoid (24%) or scirrhous (2%) growth patterns. Histologic features related to neuroendocrine differentiation, such as nuclear molding (56%), perilobular pseudopalisading (18%), and rosette formation (15%), were identified. Immunohistochemically, cytokeratin 7 and 20 were expressed in 19 (56%) and 8 (24%) cases, respectively. Loss of Rb1 expression and concomitant overexpression of p16 were observed in 25 (74%) cases. No BRAF mutations were identified in any of the 34 NECs. For survival analysis, the 1-, 3-, and 5-year overall survival rates were 64%, 35%, and 19%, respectively. In a multivariate analysis, the receipt of adjuvant chemoradiation therapy was identified as the only independent prognostic factor associated with the overall survival rate. The 1- and 3-year overall survival rates of patients with NECs were poorer for patients with poorly differentiated adenocarcinoma of the gallbladder (P<0.001). The complete resection and application of postoperative adjuvant therapy may influence a better clinical outcome in patients with NEC of the gallbladder.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/patologia , Neoplasias da Vesícula Biliar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética
9.
Toxicol Lett ; 333: 140-149, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755622

RESUMO

Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.


Assuntos
Asbestos Serpentinas/toxicidade , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Poluentes Ambientais/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Asbestos Serpentinas/química , Líquido da Lavagem Broncoalveolar/citologia , China , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/metabolismo , Poluentes Ambientais/química , Expressão Gênica/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibras Minerais/toxicidade , Proteínas Proto-Oncogênicas c-fos/genética , Ratos Wistar , Proteína Supressora de Tumor p53/genética
10.
Am J Physiol Endocrinol Metab ; 319(2): E447-E454, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32691630

RESUMO

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated ß-galactosidase (SA-ß-Gal) staining, and quantitative (q)RT-PCR. Independently of the endurance training status, TIF levels (+35%, P < 0.001) and the percentage of SA-ß-Gal-positive cells (+30%, P < 0.05) were higher in cultured satellite cells of older compared with younger subjects. p16 (4- to 5-fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%, P = 0.009). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%, P = 0.011) and tended to have lower TNF-α mRNA levels (-40%, P = 0.10) compared with the sedentary subjects. All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared with younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.


Assuntos
Envelhecimento/fisiologia , Treino Aeróbico , Inflamação/prevenção & controle , Músculo Esquelético/fisiologia , Resistência Física/fisiologia , Homeostase do Telômero/fisiologia , Idoso , Senescência Celular/genética , Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Masculino , Músculo Esquelético/química , Músculo Esquelético/citologia , RNA Mensageiro/análise , Células Satélites de Músculo Esquelético/fisiologia , Células Satélites de Músculo Esquelético/ultraestrutura , Telômero/fisiologia , Telômero/ultraestrutura , Adulto Jovem , beta-Galactosidase/análise
11.
Environ Sci Pollut Res Int ; 27(25): 31269-31277, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32488710

RESUMO

Esophageal cancer is the eighth most common cancer and the sixth most frequent cause of cancer mortality worldwide. Exposure to polycyclic aromatic hydrocarbons formed by incomplete combustion of organic matter is an important risk factor. Genetic polymorphisms in genes encoding PAH-metabolizing enzymes like glutathione S-transferases (GSTM1, GSTP1, GSTT1) which conjugate glutathione to PAHs for reduction of oxidative stress may affect an individual's response to PAH exposure. Genomic DNA from 50 esophageal squamous cell carcinoma patients extracted from peripheral blood. PCR-RFLP technique was employed to determine GSTM1, GSTT1, and GSTP1 polymorphisms. Aberrant promoter methylation of CDKN2A was applied by methylation-specific PCR technique. Concentration of urinary 1-hydroxypyrene was determined using a HPLC system. About 38.7% showed the null GSTM1 genotype (54% cases and 13% controls), 23.7% showed GSTT1 null genotype (30% cases and 13% controls), and 62.5% were GSTP1 A/A genotype (66% cases and 56% controls). Polymorphic variants of GSTM1 and GSTT1 were significantly associated with aberrant methylation of CDKN2A gene. The null state of GSTT1 was significantly associated with high concentrations of 1-OHP in urea (p < 0.01). There was significant association between methylated states of CDKN2A and high concentrations of 1-OHP in urine (p < 0.01). We identified significant association between polymorphism of GSTs genes and epigenetic silencing of tumor suppressor gene CDKN2A in esophageal squamous cell carcinoma.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Estudos de Casos e Controles , Epigênese Genética , Genes p16 , Predisposição Genética para Doença , Genótipo , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Humanos , Polimorfismo Genético , Fatores de Risco
12.
Nat Commun ; 11(1): 2711, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483135

RESUMO

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia
13.
PLoS One ; 15(6): e0235065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584870

RESUMO

INTRODUCTION: Human papillomavirus (HPV) infection is associated with the development of anogenital and head and neck cancers. In recent years a potential role of HPV in colorectal cancer (CRC) has been suggested. OBJECTIVE: To investigate the presence of HPV in colorectal carcinomas and to study the role of p16INK4a as a marker of transcriptionally active HPV infection. In addition, to investigate the correlation between these findings and the CRC prognostic factors. METHODS: Case control study with 92 cases of colorectal cancers, 75 controls of normal tissue adjacent to the tumor, and 30 controls of precursor lesions, including polyps and colorectal adenomas. Paraffinized samples were used, HPV detection and genotyping were performed by PCR and reverse hybridization by using the INNO LIPA kit, with SPF10 plus primers. The expression of the p16INK4a protein was investigated using immunohistochemistry. Data analysis was performed using descriptive, univariate statistics and survival curves were calculated by using the Kaplan Meier and log-rank method. RESULTS: HPV was detected in 13% of the cases and the most prevalent genotype was HPV 16. HPV DNA was not detected in either control groups. The high expression of p16INK4a was observed in 30% of the cases, but it was not associated to the presence of HPV. The overall survival was 53.3% and was influenced by prognostic factors such as later stage, lymph node and distant metastasis. CONCLUSIONS: Based on these results, HPV is unlikely to be involved in colorectal carcinogenesis and p16INK4a expression is not a relevant marker of transcriptionally active HPV infection in CRC.


Assuntos
Neoplasias Colorretais , Inibidor p16 de Quinase Dependente de Ciclina , Regulação Neoplásica da Expressão Gênica , Papillomavirus Humano 16 , Infecções por Papillomavirus , Adulto , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/virologia , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia
14.
Chirurg ; 91(8): 642-649, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32405728

RESUMO

The understanding of the development of pancreatic cancer has undergone considerable development over the last two decades. This is mainly due to the progress and use of methods for molecular biological analysis of pancreatic carcinomas. There is now a fundamental understanding with respect to the genetic drivers for the development of pancreatic cancer and the correlation with clinical data as well as the classification of different genetic characteristics of individual tumors even enables an estimation of the prognosis in some cases. The most common mutation in ductal adenocarcinoma, which if found in >90% of tumors, is the mutation of the KRAS oncogene. The other three, CDKN2A, p53 and SMAD4, are all tumor suppressor genes and are mutated in approximately 90%, 70% and 50% of carcinomas, respectively. In addition, genetic mutations predisposing to pancreatic cancer have been identified. Among the most important are BRCA2, p16/CDKN2A, STK11, PRSS1, PALP2, FANCC, FANCG and ATM. The classification of different subtypes and the knowledge of individual mutations (especially BRCA) can also be used to assess the response to treatment in individual cases. This applies to "conventional" combination chemotherapies (especially FOLFIRINOX) and also to targeted treatment approaches with tyrosine kinase inhibitors, PARP inhibitors and PD­1 inhibitors. If knowledge about the course of the disease and decisions on individual therapies become established in everyday clinical practice in the future, this may also have a decisive impact on surgery as the most important pillar of curative treatment. This ranges from the increased achievement of secondary operability to the expansion of indications with respect to resection even in patients with metastases.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
15.
Technol Cancer Res Treat ; 19: 1533033820920969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32372692

RESUMO

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.


Assuntos
Carcinoma Ductal Pancreático/genética , Mutação , Neoplasias Pancreáticas/genética , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Smad4/genética , Proteína Supressora de Tumor p53/genética
16.
PLoS One ; 15(5): e0232474, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374757

RESUMO

BACKGROUND: In Brazil, penile cancer (PC) is not uncommon. The highest incidence of PC is in the North and Northeast of the country. In addition to phimosis, the Human Papillomavirus (HPV) and Epstein-Baar Virus (EBV) infections are also related as risk factors for PC. The overexpression of p16INK4a is a surrogate sensitive marker of HPV infection in PC. OBJECTIVES: To correlate p16INK4a overexpression and HPV infection status with EBV infection in a series of PC patients from the Amazon region. METHODS: Tumor tissues from 47 PC cases were analyzed for the presence of HPV and EBV DNA by PCR. All PC patients were diagnosed between 2013 and 2018 at a public reference cancer center hospital in Manaus, Amazonas-Brazil. HPV was genotyped using E7 HPV16/HPV18 type-specific real-time PCR and the PapilloCheck® HPV-Screening assay. p16INK4a expression was evaluated by immunohistochemistry using the automated Ventana® BenchMark Ultra. RESULTS: The mean age of patients at the time of diagnosis was 57.4 years ±SD 17.8 ranging from 20 to 90 years old. Most of the patients (64%) came from rural areas of the Amazonas State. Thirty patients had phimosis (64%). Among the patients with phimosis, 43% (13/30) underwent circumcision, three during childhood and 10 in adulthood. 60% of the patients were smokers or ex-smokers. HPV infection was observed in 45% (21/47) of cases. HPV16 was detected in 13 patients (61%). Other HPV types detected were HPV 6, 11, 42, 51, 53, 68 and 44/55. EBV infection was observed in 30% (14/47) of the patients with PC. Co-infection with HPV and EBV was observed in 28% (6/21) cases. p16INK4a was only investigated in 26 samples. The p16INK4a overexpression was observed exclusively in HPV 16 positive cases and four HPV negative cases. In the survival analysis, the follow-up time was 35.4 months/patient. The mortality rate during the follow up time was 38%. CONCLUSIONS: p16INK4a positivity presented a high correlation to HPV 16 DNA detection, reinforcing its use as a surrogate marker for HPV-driven cancers. Infection with EBV was quite frequent and its role in epithelial penile oncogenesis needs to be demonstrated.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Infecções por Vírus Epstein-Barr/complicações , Papillomaviridae , Infecções por Papillomavirus/complicações , Neoplasias Penianas/etiologia , Neoplasias Penianas/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , DNA Viral/genética , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/virologia , Marcadores Genéticos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Neoplasias Penianas/epidemiologia , Fatores de Risco , Regulação para Cima , Adulto Jovem
17.
Hematol Oncol ; 38(4): 446-455, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32472610

RESUMO

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Genoma Humano , Linfoma de Célula do Manto/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Terapia Combinada , Ciclina D1/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Prospectivos , Transplante de Células-Tronco , Taxa de Sobrevida , Translocação Genética , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Genoma
18.
J Surg Res ; 254: 147-153, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32445930

RESUMO

BACKGROUND: For the past 30 y, the incidence rate of malignant melanoma has risen steadily. Ultraviolet radiation exposure has been identified as the most prevalent modifiable risk factor for melanoma. Here, next-generation sequencing was used to analyze the relationship between multiple sun exposure factors and select cancer-related genes to determine the relationship of sun exposure on the molecular profiles of melanomas. METHODS: The collection and analysis of study samples were approved by the institutional review board. The patient cohort consisted of 173 patients whose melanoma tissue samples underwent next-generation sequencing analysis for somatic mutations of 50 cancer-related genes. Univariate and multivariate analyses were conducted. RESULTS: Patients with a history of blistering sunburn had an absolute mutation incidence of 1.67 mutations per patient, compared with patients without a history of blistering sunburn, who had an absolute mutation incidence of 1.16 mutations per patient (P = 0.028). A BRAF mutation was found in more tumors of patients who reported visiting a tanning salon (57.14%), compared with those who had not (18.75%; P = 0.0463). Patients with a previous history of skin cancer were more likely to have a CDKN2A mutation (20.83%), compared with those without a previous history of skin cancer (7.76%; P = 0.0292). CONCLUSIONS: The trends seen in the molecular profiles of melanomas with respect to various sun exposure factors suggest that sun exposure impacts genetic makeup. Considering the increase in absolute mutation incidence in patients with a history of blistering sunburn suggests that additional genes may contribute to the pathology of malignancy. Future studies will use the unique molecular profiles of melanomas to personalize patient treatments.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Melanoma/genética , Mutação/genética , Neoplasias Cutâneas/genética , Luz Solar/efeitos adversos , Raios Ultravioleta/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/epidemiologia , Banho de Sol/estatística & dados numéricos , Queimadura Solar/genética , Curtume , Proteína Supressora de Tumor p53/genética
19.
Nat Commun ; 11(1): 1894, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313009

RESUMO

Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Segunda Neoplasia Primária/genética , Neoplasias Uveais/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Dosagem de Genes , Técnicas de Silenciamento de Genes , Humanos , Linfócitos , Linfócitos do Interstício Tumoral/patologia , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mutação , Segunda Neoplasia Primária/imunologia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Prognóstico , Análise de Sequência de DNA , Transcriptoma , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/imunologia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia
20.
Gynecol Oncol ; 157(2): 357-366, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156473

RESUMO

OBJECTIVE: Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. METHODS: A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. RESULTS: We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. CONCLUSIONS: Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias Uterinas/genética , Adulto , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Amplificação de Genes , Rearranjo Gênico , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/patologia
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