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1.
N Engl J Med ; 380(22): 2095-2103, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31141631

RESUMO

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adenina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Leucemia Linfocítica Crônica de Células B/genética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Neutropenia/induzido quimicamente , Piperidinas , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Sulfonamidas/efeitos adversos
2.
Cancer ; 122(12): 1836-43, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27018785

RESUMO

BACKGROUND: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


Assuntos
Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular/fisiologia , Criança , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Células-Tronco Neoplásicas/patologia , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
3.
Mol Carcinog ; 53(9): 711-21, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23661430

RESUMO

Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L. From reported miRNA microarray studies on PDA and predicted miRNA targets, we identified seven aberrantly upregulated miRNAs that potentially target SEL1L. We assessed the expression levels of SEL1L mRNA and the seven miRNAs in human PDA tumors and normal adjacent tissues using real-time quantitative polymerase chain reaction. Then statistical methods were applied to evaluate the association between SEL1L mRNA and the miRNAs. Furthermore, the interaction was explored by functional analysis, including luciferase assay and transient miRNA overexpression. SEL1L mRNA expression levels were found to correlate inversely with the expression of hsa-mir-143, hsa-mir-155, and hsa-mir-223 (P < 0.0001, P < 0.0001, and P = 0.002, respectively). As the number of these overexpressed miRNAs increased, SEL1L mRNA expression progressively decreased (Ptrend = 0.001). Functional analysis revealed that hsa-mir-155 acted as a suppressor of SEL1L in PDA cell lines. Our study combined statistical analysis with biological approaches to determine the relationships between several miRNAs and the SEL1L gene. The finding that the expression of the putative tumor suppressor SEL1L is repressed by upregulation of hsa-mir-155 helps to elucidate the mechanism for SEL1L downregulation in some human PDA cases. Our results suggest a role for specific miRNAs in the pathogenesis of PDA and indicate that miRNAs have potential as therapeutic targets for PDA.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Proteínas/metabolismo , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Luciferases/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Análise Serial de Proteínas , Proteínas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Dig Dis Sci ; 59(5): 968-75, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24248418

RESUMO

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in the United States. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease. AIM: We utilized the reverse-phase protein assay (RPPA) to identify differentially expressed biomarker proteins in tumors and matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients. METHODS: The antibody panel used for the RPPA included 130 key proteins involved in various cancer-related pathways. The paired t test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted p values were calculated to take into account the effect of multiple comparisons. RESULTS: After correcting for multiple comparisons, we found 19 proteins that had statistically significant differences in expression between matched pairs. However, only four (AKT, ß-catenin, GAB2, and PAI-1) of them met the conservative criteria (both a q value <0.05 and a fold-change of ≥3/2 or ≤2/3) to be considered differentially expressed. Overexpression of AKT, ß-catenin, and GAB2 in pancreatic cancer tissues identified by RPPA has also been further confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions. CONCLUSION: GAB2, a newly identified protein in pancreatic cancer, may provide additional insight into this cancer's pathogenesis. Future studies in a larger population are warranted to further confirm our results.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Análise Serial de Proteínas/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Proteômica , Transcriptoma
5.
Carcinogenesis ; 34(2): 299-306, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23125224

RESUMO

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10(-4)). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Texas/epidemiologia , Adulto Jovem
6.
BMC Gastroenterol ; 13: 67, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23590285

RESUMO

BACKGROUND: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury. METHODS: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases. RESULTS: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects. CONCLUSION: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.


Assuntos
Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Quinases Ativadas por AMP , Animais , Carcinoma Hepatocelular/induzido quimicamente , Transformação Celular Neoplásica/genética , Dietilnitrosamina , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Hepatócitos/metabolismo , Humanos , Proteínas Klotho , Fígado/metabolismo , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/induzido quimicamente , Masculino , Proteínas de Membrana/genética , Camundongos , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT3/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Mol Carcinog ; 51(5): 433-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21656579

RESUMO

SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single-nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer's disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA. We analyzed DNA samples from 497 Caucasian patients with pathologically confirmed primary PDA. Of these, 98 had been enrolled in a clinical trial of neoadjuvant chemo-radiotherapy and 77 of the 98 had subsequently undergone pancreaticoduodenectomy (PD). We performed Kaplan-Meier analysis to evaluate the correlation between different SNP genotypes and age at diagnosis, survival time after diagnosis, and survival time after PD. In nonsmokers, we found a significant difference in median age at diagnosis between variant genotypes (AG/GG) carriers and wild-type genotype (AA) carriers (58 vs. 62 yr; log-rank test, P = 0.017). Patients with variant genotypes also showed an increased hazard ratio (HR) of 1.45 [95% confidence interval (CI), 1.07-1.97] relative to wild-type genotype. Among the patients in the clinical trial, the variant genotypes carriers had a median post-PD survival time that was 34.7 months shorter than wild-type genotype carriers (log-rank test, P = 0.019; HR, 1.91; 95% CI, 1.09-3.34). Our results suggest that the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. In addition, this SNP may serve as a prognostic marker in PDA patients who undergo the same or similar treatment as the clinical trials.


Assuntos
Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Proteínas/genética , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Fumar , População Branca
8.
JAMA Oncol ; 7(8): 1213-1219, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34110383

RESUMO

IMPORTANCE: Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax. OBJECTIVE: To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax. DESIGN, SETTING, AND PARTICIPANTS: A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older. INTERVENTIONS: Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4. MAIN OUTCOMES AND MEASURES: Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate. RESULTS: Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02756897.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos Bicíclicos Heterocíclicos com Pontes , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperidinas , Sulfonamidas
9.
Clin Cancer Res ; 14(4): 1167-71, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18281551

RESUMO

PURPOSE: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have generated Lkb1+/- mice, which model human PJS. Rapamycin and its analogues are promising preventive and therapeutic agents that specifically inhibit signaling from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has been associated with PJS. The objective of the study is to investigate the efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/- mice. EXPERIMENTAL DESIGN: We initiated a trial of rapamycin in Lkb1+/- mice at 9 months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes and tumor burden. To examine the effect of rapamycin on mTOR signaling, phosphorylation levels of S6 were evaluated by immunostaining. RESULTS: We observed a significant decrease in mean tumor burden (Student's t test, P = 0.023) as well as total tumor burden in rapamycin-treated group compared with control group. Comparison of the polyp size observed in both rapamycin-treated and control groups showed that rapamycin efficiently decreased the tumor burden of large polyps (> 8 mm). This inhibition of rapamycin was associated with a decrease in phosphorylated S6 levels in the polyps. CONCLUSIONS: Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.


Assuntos
Imunossupressores/uso terapêutico , Síndrome de Peutz-Jeghers/tratamento farmacológico , Proteínas Quinases/efeitos dos fármacos , Sirolimo/uso terapêutico , Proteínas Quinases Ativadas por AMP , Animais , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Síndrome de Peutz-Jeghers/patologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR
10.
Clin Cancer Res ; 13(10): 3100-4, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17505013

RESUMO

PURPOSE: Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer. EXPERIMENTAL DESIGN: We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender. RESULTS: Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P=0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P=0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found. CONCLUSIONS: Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Pancreáticas/diagnóstico , Proteínas Serina-Treonina Quinases/genética , Fatores Etários , Aurora Quinases , Diagnóstico Precoce , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Neoplasias Pancreáticas/genética , Polimorfismo Genético , Risco , População Branca/genética
11.
Cancer Res ; 65(24): 11297-303, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16357136

RESUMO

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1(+/-) and p53 null mice to generate Lkb1(+/-)/p53(+/-) and Lkb1(+/-)/p53(-/-) mice. Similar to the Lkb1(+/-) mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1(+/-)/p53(+/-) mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1(+/-)/p53(-/-) mice is approximately 2 months earlier than Lkb1(+/-)/p53(+/-) and Lkb1(+/-) mice, whereas the latter two show a similar time to onset which is at approximately 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.


Assuntos
Transformação Celular Neoplásica , Hamartoma/genética , Mutação , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases Ativadas por AMP , Animais , Hamartoma/patologia , Heterozigoto , Incidência , Perda de Heterozigosidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Peutz-Jeghers/patologia , Taxa de Sobrevida
12.
PLoS One ; 12(9): e0184154, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28880927

RESUMO

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.


Assuntos
Endotelina-3/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor de Endotelina B/metabolismo , Fator de Células-Tronco/metabolismo , Aterosclerose/patologia , Linhagem Celular Tumoral , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Motilidade Gastrointestinal , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/fisiopatologia , Homeostase , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imuno-Histoquímica , Melanoma/patologia , Plexo Mientérico/metabolismo , Invasividade Neoplásica , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais , Pele/metabolismo , Luz Solar , Fatores de Tempo , Regulação para Cima/genética , Vasodilatação
13.
Fam Cancer ; 14(2): 297-306, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25716654

RESUMO

We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of HNRNPA0 associated with elevated cancer incidence in this family (Hazard ratio = 7.20, p = 0.0004). Whole genome sequencing identified a second rare protein changing mutation of WIF1 that interacted with the HNRNPA0 variant resulting in extremely high risk for cancer in carriers of mutations in both genes (p = 1.98 × 10(-13)). Analysis of downstream targets of the mutations in these two genes showed that the HNRNPA0 mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the WIF1 variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in HNRNPA0 influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Ribonucleoproteínas Nucleares Heterogêneas/genética , Neoplasias/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único
14.
J Histochem Cytochem ; 51(12): 1665-72, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14623934

RESUMO

Germline mutations of the LKB1 gene lead to Peutz-Jeghers syndrome (PJS), which is associated with a predisposition to gastrointestinal polyposis and cancer. In this study we tested for germline mutations of LKB1 in 11 patients with PJS from nine families and analyzed the expression patterns of the LKB1 and cyclo-oxygenase-2 (COX-2) proteins in 28 Peutz-Jeghers polyps (PJPs) and five carcinomas from these patients by immunohistochemical (IHC) analysis. In eight of those families we identified seven different mutations, which consisted of two splice site mutations, two nonsense mutations, one small in-frame deletion, one frame-shift mutation, and one silent mutation. Immunostaining revealed nuclear and cytoplasmic expression of LKB1 protein in 23 PJPs and five carcinomas, nuclear expression alone in one PJP, and loss of LKB1 protein expression in four PJPs, indicating a heterogeneous LKB1 expression pattern in PJPs. Overexpression of COX-2 was detected in 23 (82%) of 28 PJPs and in all carcinomas. Despite heterogeneity in staining of LKB1 among individuals and even among samples from the same individual, we found statistically significant correlations in staining of LKB1 relative to COX-2. These results suggest that COX-2 plays a role in tumorigenesis in PJS and may therefore be considered as a potential target for PJS chemoprevention.


Assuntos
Isoenzimas/metabolismo , Síndrome de Peutz-Jeghers/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo-Oxigenase 2 , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Síndrome de Peutz-Jeghers/patologia , Proteínas Serina-Treonina Quinases/genética
15.
Clin Neurol Neurosurg ; 122: 4-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24908208

RESUMO

BACKGROUND: Low education level has been thought an important and specific risk factor for dementia. Therefore, we surveyed dementia in a highly educated population in Tianjin, China. METHODS: In total, 1324 old people (aged 55 years and over) in three cluster samples from university communities in Tianjin responded to our survey. Data from psychological tests and dementia questionnaires were analyzed. RESULTS: The prevalence of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) was 4.98%, 2.11%, and 2.27%, respectively. A history of stroke (OR=6.036), lack of fruit (OR=5.489), early parental death (OR=3.102), household financial management (OR=2.638), a history of cardiovascular disease (OR=2.434), a history of hypertension (OR=2.042), physical exercise (OR=2.556), were significantly associated with dementia in a single-factor analysis. Four independent variables were entered in a regression equation: early parental death (OR=6.417), lack of fruit in the diet (OR=3.919), personal stroke history (OR=3.901), and lack of physical exercise (OR=2.220). CONCLUSION: The prevalence of dementia was lower in highly educated elderly people in universities in Tianjin than in the general population. Risk factors for dementia included disease history, living habits, and early parental death, so corresponding interventions are required.


Assuntos
Demência/epidemiologia , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Escolaridade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
16.
Nat Cell Biol ; 16(1): 108-17, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24362629

RESUMO

The Hippo-YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo-YAP signalling cascade.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Testes Genéticos , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Animais , Linhagem Celular Tumoral , Ativação Enzimática , Técnicas de Silenciamento de Genes , Genes Reporter , Células HEK293 , Via de Sinalização Hippo , Humanos , Camundongos , Mutação/genética , Neoplasias/enzimologia , Neoplasias/patologia , Transporte Proteico , Interferência de RNA , Transdução de Sinais/genética , Especificidade por Substrato , Fatores de Transcrição , Proteínas de Sinalização YAP
17.
J Cancer Res Clin Oncol ; 139(7): 1241-50, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23604467

RESUMO

PURPOSE: Lynch syndrome (LS) is a common inherited predisposition to colorectal cancer (CRC). In LS patients, CRC is predominantly located in the right colon, as opposed to sporadic CRC, which usually affects the left colon or rectum. Previous studies have demonstrated a clear distinction in gene expression between sporadic CRC and normal colon at different locations in the colorectum. However, little is known about LS gene expression profiles in different areas of the colorectum. Here, we compared the protein expression profiles for normal colorectal samples among different locations as well as between adenomas and matched normal tissue in LS. METHODS: Protein from 33 tissue samples (27 normal tissues and 6 adenomas) from 9 patients with LS was extracted for reverse-phase protein array (RPPA) analysis. The antibody panel used for RPPA included 109 key proteins involved in various cancer-related pathways. Cluster 3.0 was used for unsupervised and supervised clustering analysis. RESULTS: IGF1R and COL6A1 were expressed significantly differently between the normal right and normal left colon (q < 0.05); FN1, COL6A1, and IGF1R were expressed significantly differently between the normal right colon and normal rectum (q < 0.05). In the adenomas and matched normal tissue, PEA-15 was the only protein with significantly different expression (q < 0.05). CONCLUSION: We found differences in protein expression between normal tissues from the right colon, left colon, and rectum as well as between adenomas and matched normal tissue. However, those differences should be further confirmed in a larger sample size.


Assuntos
Adenoma/metabolismo , Colo/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Proteoma/metabolismo , Reto/metabolismo , Adenoma/patologia , Cromatografia de Fase Reversa , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Projetos Piloto , Proteoma/isolamento & purificação , Análise Serial de Tecidos
18.
Cancer Epidemiol Biomarkers Prev ; 22(2): 251-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23221128

RESUMO

BACKGROUND: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. METHODS: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. RESULTS: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)). CONCLUSIONS: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. IMPACT: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.


Assuntos
Biomarcadores Tumorais/genética , Negro ou Afro-Americano/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/etiologia , Polimorfismo de Nucleotídeo Único/genética , Adenocarcinoma/etnologia , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Escamosas/etnologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase , Prognóstico , Proteínas/genética , Receptores Nicotínicos/genética , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/etnologia , Carcinoma de Pequenas Células do Pulmão/etiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Telomerase/genética
19.
PLoS One ; 7(7): e41118, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22815934

RESUMO

Orientation of mitotic spindles plays an integral role in determining the relative positions of daughter cells in a tissue. LKB1 is a tumor suppressor that controls cell polarity, metabolism, and microtubule stability. Here, we show that germline LKB1 mutation in mice impairs spindle orientation in cells of the upper gastrointestinal tract and causes dramatic mislocalization of the LKB1 substrate AMPK in mitotic cells. RNAi of LKB1 causes spindle misorientation in three-dimensional MDCK cell cysts. Maintaining proper spindle orientation, possibly mediated by effects on the downstream kinase AMPK, could be an important tumor suppressor function of LKB1.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Células Epiteliais/citologia , Mutação , Animais , Caderinas/metabolismo , Colágeno/química , Cães , Combinação de Medicamentos , Genes Supressores de Tumor , Laminina/química , Camundongos , Microscopia de Fluorescência/métodos , Microtúbulos/metabolismo , Mitose , Proteoglicanas/química , Interferência de RNA , Fuso Acromático , Proteína da Zônula de Oclusão-1/metabolismo
20.
Fam Cancer ; 11(3): 441-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22714864

RESUMO

The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P ≤ 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Mutação , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Heterozigoto , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Melanoma/epidemiologia , Melanoma/genética , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Sistema de Registros , Texas , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
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